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Showing 1 - 200 of 3562 Journals sorted alphabetically
16 de Abril     Open Access  
3D Printing in Medicine     Open Access   (Followers: 1)
AADE in Practice     Hybrid Journal   (Followers: 5)
ABCS Health Sciences     Open Access   (Followers: 3)
Abia State University Medical Students' Association Journal     Full-text available via subscription  
ACIMED     Open Access   (Followers: 1)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 41)
Acta Bio Medica     Full-text available via subscription   (Followers: 2)
Acta Bioethica     Open Access  
Acta Bioquimica Clinica Latinoamericana     Open Access   (Followers: 1)
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Acta Informatica Medica     Open Access   (Followers: 1)
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Acta Scientiarum. Health Sciences     Open Access   (Followers: 1)
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Addiction Science & Clinical Practice     Open Access   (Followers: 6)
Addictive Behaviors Reports     Open Access   (Followers: 8)
Adıyaman Üniversitesi Sağlık Bilimleri Dergisi / Health Sciences Journal of Adıyaman University     Open Access  
Adnan Menderes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi     Open Access  
Advanced Biomedical Research     Open Access  
Advanced Health Care Technologies     Open Access   (Followers: 4)
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Advances in Life Course Research     Hybrid Journal   (Followers: 8)
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Advances in Regenerative Medicine     Open Access   (Followers: 2)
Advances in Skeletal Muscle Function Assessment     Open Access  
Advances in Therapy     Hybrid Journal   (Followers: 5)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
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African Health Sciences     Open Access   (Followers: 2)
African Journal of Biomedical Research     Open Access  
African Journal of Clinical and Experimental Microbiology     Open Access   (Followers: 1)
African Journal of Laboratory Medicine     Open Access   (Followers: 2)
African Journal of Medical and Health Sciences     Open Access   (Followers: 2)
African Journal of Trauma     Open Access   (Followers: 1)
Afrimedic Journal     Open Access   (Followers: 2)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 8)
AJOB Primary Research     Partially Free   (Followers: 3)
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Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access   (Followers: 1)
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 2)
Alpha Omegan     Full-text available via subscription  
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
American Journal of Biomedical Engineering     Open Access   (Followers: 11)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 7)
American Journal of Chinese Medicine, The     Hybrid Journal   (Followers: 4)
American Journal of Clinical Medicine Research     Open Access   (Followers: 7)
American Journal of Family Therapy     Hybrid Journal   (Followers: 11)
American Journal of Law & Medicine     Full-text available via subscription   (Followers: 11)
American Journal of Lifestyle Medicine     Hybrid Journal   (Followers: 5)
American Journal of Managed Care     Full-text available via subscription   (Followers: 11)
American Journal of Medical Case Reports     Open Access   (Followers: 1)
American Journal of Medical Sciences and Medicine     Open Access   (Followers: 4)
American Journal of Medicine     Hybrid Journal   (Followers: 45)
American Journal of Medicine and Medical Sciences     Open Access   (Followers: 1)
American Journal of Medicine Studies     Open Access   (Followers: 1)
American Journal of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American Journal of the Medical Sciences     Hybrid Journal   (Followers: 12)
American Journal on Addictions     Hybrid Journal   (Followers: 8)
American medical news     Free   (Followers: 3)
American Medical Writers Association Journal     Full-text available via subscription   (Followers: 5)
Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 5)
Anales de la Facultad de Medicina     Open Access  
Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
Analgesia & Resuscitation : Current Research     Hybrid Journal   (Followers: 5)
Anatolian Clinic the Journal of Medical Sciences     Open Access  
Anatomical Science International     Hybrid Journal   (Followers: 2)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1)
Anatomy     Open Access  
Anatomy Research International     Open Access   (Followers: 2)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3)
Ankara Medical Journal     Open Access   (Followers: 2)
Ankara Üniversitesi Tıp Fakültesi Mecmuası     Open Access  
Annales de Pathologie     Full-text available via subscription  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 1)
Annals of Anatomy - Anatomischer Anzeiger     Hybrid Journal   (Followers: 2)
Annals of Bioanthropology     Open Access   (Followers: 4)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Biomedical Sciences     Full-text available via subscription   (Followers: 3)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 10)
Annals of Family Medicine     Open Access   (Followers: 12)
Annals of Ibadan Postgraduate Medicine     Open Access  
Annals of Medical and Health Sciences Research     Open Access   (Followers: 7)
Annals of Medicine     Hybrid Journal   (Followers: 12)
Annals of Medicine and Surgery     Open Access   (Followers: 7)
Annals of Microbiology     Hybrid Journal   (Followers: 11)
Annals of Nigerian Medicine     Open Access   (Followers: 1)
Annals of Saudi Medicine     Open Access  
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5)
Annals of The Royal College of Surgeons of England     Full-text available via subscription   (Followers: 3)
Annual Reports in Medicinal Chemistry     Full-text available via subscription   (Followers: 7)
Annual Reports on NMR Spectroscopy     Full-text available via subscription   (Followers: 4)
Annual Review of Medicine     Full-text available via subscription   (Followers: 16)
Anthropological Review     Open Access   (Followers: 23)
Anthropologie et santé     Open Access   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibodies     Open Access   (Followers: 2)
Antibody Technology Journal     Open Access   (Followers: 1)
Anuradhapura Medical Journal     Open Access  
Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
Apmis     Hybrid Journal   (Followers: 1)
Apparence(s)     Open Access   (Followers: 1)
Applied Clinical Research, Clinical Trials and Regulatory Affairs     Hybrid Journal  
Applied Medical Informatics     Open Access   (Followers: 10)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
Arak Medical University Journal     Open Access  
Archive of Clinical Medicine     Open Access   (Followers: 1)
Archive of Community Health     Open Access   (Followers: 1)
Archives Medical Review Journal / Arşiv Kaynak Tarama Dergisi     Open Access  
Archives of Medical and Biomedical Research     Open Access   (Followers: 3)
Archives of Medical Laboratory Sciences     Open Access   (Followers: 1)
Archives of Medicine and Health Sciences     Open Access   (Followers: 3)
Archives of Medicine and Surgery     Open Access  
Archives of Trauma Research     Open Access   (Followers: 3)
Archivos de Medicina (Manizales)     Open Access  
ArgoSpine News & Journal     Hybrid Journal  
Arquivos Brasileiros de Oftalmologia     Open Access  
Arquivos de Ciências da Saúde     Open Access  
Arquivos de Medicina     Open Access  
Ars Medica : Revista de Ciencias Médicas     Open Access  
ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 12)
Arterial Hypertension     Open Access   (Followers: 1)
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 13)
Artificial Organs     Hybrid Journal   (Followers: 1)
ASHA Leader     Open Access  
Asia Pacific Family Medicine     Open Access   (Followers: 1)
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 10)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Biomedicine     Open Access   (Followers: 2)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 3)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 2)
Asian Journal of Scientific Research     Open Access   (Followers: 3)
Asian Journal of Transfusion Science     Open Access   (Followers: 1)
Asian Medicine     Hybrid Journal   (Followers: 5)
Asian Pacific Journal of Cancer Prevention     Open Access  
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Audiology - Communication Research     Open Access   (Followers: 9)
Auris Nasus Larynx     Full-text available via subscription  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 1)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 3)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 3)
Bangladesh Journal of Medical Physics     Open Access  
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)

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Journal Cover
Annual Reports in Medicinal Chemistry
Journal Prestige (SJR): 0.33
Citation Impact (citeScore): 1
Number of Followers: 7  
  Full-text available via subscription Subscription journal
ISSN (Print) 0065-7743
Published by Elsevier Homepage  [3159 journals]
  • Chapter Ten Chemical Biology in Drug Discovery
    • Authors: M. Paola Castaldi; Andrea Zuhl; Piero Ricchiuto; J. Adam Hendricks
      Pages: 335 - 370
      Abstract: Publication date: 2017
      Source:Annual Reports in Medicinal Chemistry, Volume 50
      Author(s): M. Paola Castaldi, Andrea Zuhl, Piero Ricchiuto, J. Adam Hendricks
      Chemical biology is the broad discipline at the interface of chemistry and biology that has contributed many important advancements to our ability to perturb and probe biological functions. In this chapter, we focus on describing chemical biology methods for target identification, target engagement, and target validation with demonstrative examples from the last few years.

      PubDate: 2017-11-21T07:32:13Z
      DOI: 10.1016/bs.armc.2017.08.009
      Issue No: Vol. 50 (2017)
  • Chapter One A Personal Essay
    • Authors: John J. Baldwin
      Pages: 3 - 9
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): John J. Baldwin

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00001-8
      Issue No: Vol. 49 (2017)
  • Chapter Two Adventures in Medicinal Chemistry
    • Authors: William J. Greenlee
      Pages: 11 - 23
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): William J. Greenlee

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00002-x
      Issue No: Vol. 49 (2017)
  • Chapter Three Natural and Synthetic Neuroactive Steroid Modulators of
           GABAA and NMDA Receptors
    • Authors: Gabriel Martinez-Botella; Michael A. Ackley; Francesco G. Salituro; James J. Doherty
      Pages: 27 - 42
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Gabriel Martinez-Botella, Michael A. Ackley, Francesco G. Salituro, James J. Doherty
      Neuroactive steroids (NASs) are a family of steroid-based compounds of both natural and synthetic origin, which have been shown to impact central nervous system function through allosteric modulation of the GABA(γ-aminobutyric acid)A receptor and the NMDA (N-methyl-d-aspartic acid) class of glutamate receptors. Respectively, these are two of the major inhibitory and excitatory neurotransmitter receptor families involved in synaptic transmission in the brain. Research over recent years has demonstrated that these receptors can be either positively (PAM) or negatively (NAM) allosterically modulated by NAS compounds, an action mediated through binding to allosteric sites. The focus of this report is to briefly review endogenous and synthetic NASs that target GABAA and NMDA receptors.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00003-1
      Issue No: Vol. 49 (2017)
  • Chapter Four Development of LRRK2 Kinase Inhibitors for Parkinson's
    • Authors: Paul Galatsis; Jaclyn Henderson; Bethany L. Kormos; Warren D. Hirst
      Pages: 43 - 58
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Paul Galatsis, Jaclyn Henderson, Bethany L. Kormos, Warren D. Hirst
      Parkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disorder after Alzheimer's disease. The etiology of PD is complex but the most common phenotype is the loss of dopaminergic neurons of the substantia nigra leading to the clinical symptoms of bradykinesia, resting tremors, rigidity, and postural instability. The most common genetic cause of autosomal dominant PD is mutations in leucine-rich repeat kinase 2 (LRRK2) which accounts for 1% of sporadic and 4% of familial cases. The G2019S mutation is the most common in LRRK2 and occurs in the DYG motif of the kinase domain, where it appears to increase its kinase activity. Consequently, a great deal of effort has been directed toward identifying potent LRRK2 kinase inhibitors with a biopharmaceutical profile congruent with clinical evaluation and this report summarizes efforts in this regard.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00004-3
      Issue No: Vol. 49 (2017)
  • Chapter Five Stimulating Neurotrophin Receptors in the Treatment of
           Neurodegenerative Disorders
    • Authors: Gunnar Nordvall; Pontus Forsell
      Pages: 59 - 73
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Gunnar Nordvall, Pontus Forsell
      Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are currently lacking disease-modifying treatments. A substantial body of evidence links increases in neurotrophin (NT) signaling in neurodegenerative disorders with biological mechanisms that could have a positive effect on disease outcome. NTs like NGF and BDNF signal through Trk receptors. This signaling is of high importance to support neuronal survival, differentiation, neurogenesis, and synaptic plasticity. The poor pharmacokinetics of NTs makes them unsuitable as drugs. In addition, the NTs have pleiotropic effects that may give side effects. Therefore, the identification of small molecules that promote NT signaling is of increasing interest. Such small-molecule activators of NT signaling will support neuronal survival in the CNS, and thus they could possibly function as disease modifiers. Herein, we review the current status of small-molecule compounds that are able to activate NT receptors.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00005-5
      Issue No: Vol. 49 (2017)
  • Chapter Six Small-Molecule Modulators of GPR40 (FFA1)
    • Authors: Sean P. Brown; Joshua P. Taygerly
      Pages: 77 - 86
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Sean P. Brown, Joshua P. Taygerly
      GPR40 (also known as FFA1) is a G-protein-coupled receptor primarily expressed in pancreatic islets and enteroendocrine cells, and activation of GPR40 has been shown to stimulate insulin secretion through a glucose-dependent mechanism. For this reason, the pharmaceutical industry has focused considerable resources on small-molecule GPR40 activators as a potential treatment for type II diabetes. This chapter details the important GPR40 activators disclosed to date, particularly focusing on clinical candidates. Additionally, two distinct classes of GPR40 activators have been discovered that bind in discreet allosteric binding pockets: partial agonists and full agonists. The differences in both chemical structure and biological efficacy between these two classes of GPR40 ligands are discussed in detail.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00006-7
      Issue No: Vol. 49 (2017)
  • Chapter Seven Recent Advances in the Development of P2Y12 Receptor
           Antagonists as Antiplatelet Agents
    • Authors: Allorie T. Caldwell; E. Blake Watkins
      Pages: 87 - 99
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Allorie T. Caldwell, E. Blake Watkins
      P2Y12 receptor antagonists are now the primary mode of treatment for acute coronary syndromes and for patients undergoing percutaneous coronary intervention with stenting. Antagonism of the receptor inhibits ADP-mediated platelet aggregation and results in a reduction in occlusive thrombotic events. Four FDA-approved agents are currently in use. Of these, clopidogrel has seen significant use in the clinic but suffers from inter-individual variation due to genetic differences in patient populations. Additionally, P2Y12 antagonists have demonstrated bleeding risks in certain patient populations. A number of structural analogs have been synthesized in an attempt to circumvent this issue while maintaining strong antiplatelet activity. Improved pharmacokinetic properties as well as potent antiplatelet activity of several of these agents warranted further examination.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00007-9
      Issue No: Vol. 49 (2017)
  • Chapter Eight Current Approaches to the Treatment of Atrial Fibrillation
    • Authors: Heather Finlay
      Pages: 101 - 113
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Heather Finlay
      Atrial fibrillation (AF) is a condition characterized by rapid and irregular sinus rhythm which leads to a higher incidence of stroke and increased mortality. AF affects approximately 1% of the worldwide population, and despite significant advances in anticoagulation therapy, AF patients remain in abnormal sinus rhythm. There is a demonstrated benefit to restoring and maintaining normal sinus rhythm in addition to preventing thromboembolic events, and the discovery of anti-arrhythmic agents with improved efficacy and safety has been a continued and active area of research in the pharmaceutical industry. Recent clinical and preclinical advances in the atrial-selective I Kur and I KAch ion channel targets are summarized in this review covering disclosures from 2010 to 2014.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00008-0
      Issue No: Vol. 49 (2017)
  • Chapter Nine Advances in the Discovery of Small-Molecule IRAK4 Inhibitors
    • Authors: John Hynes; Satheesh K. Nair
      Pages: 117 - 133
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): John Hynes, Satheesh K. Nair
      Therapeutic targeting of innate immune system pathways in chronic inflammatory diseases, such as rheumatoid arthritis and lupus, may provide additional therapies for patients afflicted with these conditions. Interleukin-1 receptor-associated kinase 4 (IRAK4), a serine/threonine kinase, is a key molecule downstream of the innate signaling toll-like receptors (TLRs). The TLRs are activated by endogenous pathogens associated with necrotic cell death and tissue damage, hallmarks of chronic inflammation. Additionally, IRAK4 is downstream of the key proinflammatory signaling IL-1 family of receptors. Several biologic IL-1-targeting therapies have been approved, and an IRAK4 inhibitor would be an attractive alternative for targeting this pathway. Finally, aberrant signaling of the IRAK4 pathway due to activating mutations in the MyD88 adaptor protein has been implicated in certain cancers. Accordingly, IRAK4 inhibitors may provide additional options for the treatment of chronic inflammatory diseases and cancers. A summary of the recent structural classes of IRAK4 inhibitors is provided.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00009-2
      Issue No: Vol. 49 (2017)
  • Chapter Ten H4 Receptor Antagonists and Their Potential Therapeutic
    • Authors: David Burns; Niu Shin; Ravi Jalluri; Wenqing Yao; Peggy Scherle
      Pages: 135 - 149
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): David Burns, Niu Shin, Ravi Jalluri, Wenqing Yao, Peggy Scherle
      The histamine H4 receptor shows generally restricted expression in immune cells and has been shown to mediate histamine induced-chemotaxis, suggesting that it may play a role in inflammation. This has led to the discovery and characterization of histamine H4 receptor antagonists from multiple chemical scaffolds. These antagonists have shown efficacy in numerous preclinical models of inflammation, further supporting the critical role of the histamine H4 receptor in inflammatory diseases, including rheumatoid arthritis, asthma, pruritis and inflammatory pain. The first histamine H4 receptor antagonists have entered into clinical trials and data are expected soon to establish the importance of targeting this receptor as a novel therapeutic in inflammation. This review focuses on the histamine H4 receptor antagonists that have been identified to date.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00010-9
      Issue No: Vol. 49 (2017)
  • Chapter Eleven Urate Crystal Deposition Disease and Gout—New
           Therapies for an Old Problem
    • Authors: Jean-Luc Girardet; Jeffrey N. Miner
      Pages: 151 - 164
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Jean-Luc Girardet, Jeffrey N. Miner
      Gout is a chronic, inflammatory arthritic condition resulting from monosodium urate crystal deposition in joints and tissues, which develop because of high levels of serum uric acid. Gout treatment includes short-term approaches for acute gout attacks (gout flares) and long-term approaches for treating hyperuricemia. Acute gout therapy focuses on rapid inhibition of pain and inflammation resulting from the inflammatory response to monosodium urate crystal deposition. Most commonly prescribed acute gout therapies in the United States are NSAIDs, colchicine, and corticosteroids. Optimal treatment of gout also includes approaches to address chronically high uric acid levels. Therapeutic approaches to address gout-associated hyperuricemia include inhibiting production of uric acid using xanthine oxidase inhibitors, degrading uric acid with recombinant uricase, and increasing uric acid excretion using older uricosuric agents and newer selective uric acid reabsorption inhibitors. The recent surge of research in this area brings with it the potential for new targets and therapeutic combinations.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00011-0
      Issue No: Vol. 49 (2017)
  • Chapter Twelve p53–MDM2 and MDMX Antagonists
    • Authors: Constantinos Neochoritis; Natalia Estrada-Ortiz; Kareem Khoury; Alexander Dömling
      Pages: 167 - 187
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Constantinos Neochoritis, Natalia Estrada-Ortiz, Kareem Khoury, Alexander Dömling
      The protein–protein interaction of the oncogene mouse double minute 2 (MDM2) and the transcription factor tumor-suppressor p53 is an emerging target in oncology, and prove of concept for their druggability has been established by the discovery of Nutlin. The approach is notably different from many classical genotoxic anticancer therapeutics and can potentially add to the future arsenal of anticancer weapons. A wealth of biochemical, cell biological, and structural biological data is available, and different small molecular weight scaffolds with impressive activities have been disclosed. The structural requirements for small-molecule MDM2 antagonist are well understood, not so for the upcoming MDMX antagonists. The recent interim results of a phase I trial reported by ROCHE on a Nutlin derivative are promising. Several compounds from other companies are moving toward advanced clinical trials.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00012-2
      Issue No: Vol. 49 (2017)
  • Chapter Thirteen Modulators of Atypical Protein Kinase C as Anticancer
    • Authors: Jonathan R.A. Roffey; Gregory R. Ott
      Pages: 189 - 206
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Jonathan R.A. Roffey, Gregory R. Ott
      The atypical protein kinase C (PKC) isoforms (zeta and iota) have recently garnered attention as therapeutic targets for oncology, metabolic diseases as well as other indications. Though the novel and classical PKC isoforms have been interrogated as therapeutic intervention points and inhibitors of these isoforms (both selective and nonselective) have advanced to the clinic, no atypical inhibitor has been validated at this level. Recent biological studies have demonstrated the direct role for atypical PKC isoforms in specific cancers and the preclinical validity of atypical PKCs as therapeutic intervention points. This review will cover the structure/function of atypical PKCs versus novel and classical PKC isoforms, the implications in disease states, focusing on oncology, and a summary of both non-ATP competitive and ATP-competitive atypical PKC inhibitors.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00013-4
      Issue No: Vol. 49 (2017)
  • Chapter Fourteen Advancement of Cell Wall Inhibitors in Mycobacterium
           tuberculosis*Present address: Sai Life Sciences Ltd, Pune, India.
    • Authors: Pravin S. Shirude; Monalisa Chatterji; Shridhar Narayanan; Pravin S. Iyer
      Pages: 209 - 220
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Pravin S. Shirude, Monalisa Chatterji, Shridhar Narayanan, Pravin S. Iyer
      Despite decades of scientific progress, tuberculosis (TB) still remains a major global health problem. The first-line and second-line anti-TB drugs include compounds that inhibit some part of Mycobacterium tuberculosis (Mtb) cell wall synthesis or metabolism. The recent understanding of “cell wall core” activity in the different stages of infection in vivo has highlighted the importance of cell wall inhibitors targeting both replicating and nonreplicating Mtb. Therefore, most of the newly discovered compounds emphasize the cell wall as the target of choice for Mtb. Drug-to-target screening approaches have identified novel targets impacting major cell wall components (e.g., DprE1, MmpL3, and others) in addition to better known targets (InhA, peptidoglycan synthesis). Novel cell wall inhibitors provide a potential new therapy to address drug-resistant TB in patients who are resistant to existing first- and second-line drugs. This review broadly describes recent advances in targeting the cell wall of Mtb, with specific focus on InhA, DprE1, MmpL3, and peptidoglycan biosynthesis.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00014-6
      Issue No: Vol. 49 (2017)
  • Chapter Fifteen Nucleosides and Nucleotides for the Treatment of Viral
    • Authors: Michael J. Sofia
      Pages: 221 - 247
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Michael J. Sofia
      Nucleosides and nucleotides have played an important role in the treatment of viral diseases. The treatment of human immunodeficiency virus (HIV) infection has seen the introduction of no less than eight nucleos(t)ides into clinical practice where they have become the cornerstone of combination therapies. Nucleos(t)ides have become the standard of care for the treatment of hepatitis B virus (HBV) infection and are rapidly emerging as the backbone of future combination regimens for the treatment of hepatitis C virus (HCV) infection. The treatment of many other viral infections such as those caused by cytomegalovirus, herpes simplex virus, Epstein–Barr virus, and varicella zoster virus rely heavily on nucleos(t)ide-based therapies. Consequently, because of the broad utility and success of these molecules in the treatment of viral diseases, efforts continue to search for novel nucleos(t)ides that can have an impact in antiviral clinical practice. This review will focus on recent developments in the field of nucleos(t)ide antiviral drug discovery and development with emphasis on HIV, HBV, HCV, and Dengue virus.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00015-8
      Issue No: Vol. 49 (2017)
  • Chapter Sixteen Advances in Inhibitors of Penicillin-Binding Proteins and
           β-Lactamases as Antibacterial Agents
    • Authors: Yong He; Jonathan Lawrence; Christopher Liu; Ning Yin
      Pages: 249 - 266
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Yong He, Jonathan Lawrence, Christopher Liu, Ning Yin
      The continued rise of multidrug-resistant bacterial infections poses a significant threat to public health and has prompted the pharmaceutical industry to reinvest in the discovery of new antibiotics with increased potency and expanded spectrum against these lethal pathogens. Although many excellent antibacterial targets exist, the penicillin-binding proteins remain the most clinically successful and most well-understood antibacterial targets currently by researchers. The classic β-lactam motif continues to be a primary driver in this field with Nth generation β-lactams as a major focus of research. In addition, the evolution of β-lactamase (BL) resistance-particularly in Gram-negative pathogens-has pushed the industry to develop both non-β-lactam inhibitors of PBPs as well as direct inhibitors of the BL enzymes themselves, dosed concurrently with a BL antibiotic. This review will summarize the most recent advances in the development of BL and non-β-lactam PBP inhibitors and the development of inhibitors of the serine and metallo-β-lactamase enzymes for treatment of bacterial infections.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00016-x
      Issue No: Vol. 49 (2017)
  • Chapter Seventeen Tumor Microenvironment as Target in Cancer Therapy
    • Authors: Reuven Reich; Claudiu T. Supuran; Eli Breuer
      Pages: 269 - 284
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Reuven Reich, Claudiu T. Supuran, Eli Breuer
      The role of the microenvironment is of critical importance during the initiation and progression of carcinogenesis, both for understanding cancer biology and exploiting new knowledge for improved diagnostics and therapeutics at the cellular and molecular level. This summary emphasizes the most dynamic aspects of the microenvironment, namely tumor promoting enzymes and their inhibition. The enzymes mentioned are matrix metalloproteinases (MMPs) degrading connective tissue and carbonic anhydrases regulating pH level in the extracellular space. Additional enzymes reviewed are ectonucleotidases, such as autotaxin (ATX), CD73, and CD39. There is a short introduction to carbamoylphosphonates, inhibitors that regulate in vivo three kinds of zinc enzymes, MMP2, CAIX, and ATX, incapacitating the cancer.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00017-1
      Issue No: Vol. 49 (2017)
  • Chapter Eighteen Novel Screening Paradigms for the Identification of
           Allosteric Modulators and/or Biased Ligands for Challenging
           G-Protein-Coupled Receptors
    • Authors: Stephan Schann; Pascal Neuville; Michel Bouvier
      Pages: 285 - 300
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Stephan Schann, Pascal Neuville, Michel Bouvier
      GPCRs have proven to be a valuable target family for drug discovery with more than 30% of marketed drugs acting through this receptor superfamily. However, numerous members remain challenging with no selective and druggable ligands being successfully developed. For these difficult targets, novel strategies consisting in developing allosteric modulators (AMs), biased ligands (BLs), or antibodies (Abs) are now emerging. These new classes of ligands are associated with advantages for the development of safer therapeutics but their identification can also prove to be challenging and novel screening paradigms are required. This chapter discusses these novel approaches for AM and BL identification and the recent identification of Abs showing AM/BL properties. Taken together, these new paradigms mark the beginning of a new GPCR drug discovery age.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00018-3
      Issue No: Vol. 49 (2017)
  • Chapter Nineteen Mer Receptor Tyrosine Kinase
    • Authors: Xiaodong Wang; Stephen Frye
      Pages: 301 - 314
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Xiaodong Wang, Stephen Frye
      Mer is a member of the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase subfamily with growth arrest specific-6 as one of its endogenous ligands. Elevated Mer activation has been strongly associated with poor prognosis and enhanced survival signaling in many human cancers. The normal biological role of Mer in regulating ingestion of apoptotic material by macrophages and epithelial cells, and the latter stages of platelet aggregation, presents therapeutic opportunities beyond oncology for a Mer-directed tyrosine kinase inhibitor. The activity of highly potent small molecule Mer inhibitors in: (1) animal models of Mer driven tumors, (2) tumors lacking Mer but sensitive to a Mer antagonist's immune stimulatory effects, (3) acute models of coagulation, and (4) enveloped virus infections will be reviewed and discussed.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00019-5
      Issue No: Vol. 49 (2017)
  • Chapter Twenty Disease-Modifying Agents for the Treatment of Cystic
    • Authors: Bradley D. Tait; John P. Miller
      Pages: 317 - 330
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Bradley D. Tait, John P. Miller
      Cystic fibrosis is a genetic disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that affect transcription, folding, trafficking, degradation, or channel opening of the protein. The lack of CFTR chloride and bicarbonate conductance results in thick mucus accumulation in the pancreas, intestines, and lungs. Treatment of CF symptoms has improved lifespan and quality of life for patients. A key unmet need is drugs targeting the underlying cause of the disease, the defective CFTR protein. The approval of ivacaftor for Class III CFTR-gating mutations demonstrates the potential to address the underlying cause of CF with small molecules. This chapter discusses recent CFTR correctors and potentiators that target defects associated with several different classes of CFTR mutations.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00020-1
      Issue No: Vol. 49 (2017)
  • Chapter Twenty-One Advancements in Stapled Peptide Drug Discovery
           & Development
    • Authors: Vincent Guerlavais; Tomi K. Sawyer
      Pages: 331 - 345
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Vincent Guerlavais, Tomi K. Sawyer
      Stapled peptides are an emerging class of drugs with a unique set of properties that fully capitalize on 25 years of genetic research to attack drivers of complex diseases, including cancer, endocrine/metabolic disorders, and inflammation. Stapling technology locks peptides into their biologically active shape and impart unprecedented pharmaceutical stability within the body. Stapled peptide drugs are derived from natural peptides and are designed to potently and specifically target protein–protein interactions both inside and outside the cell. The review highlights the first example of a potent and selective stapled peptide dual inhibitor of MDM2 and MDMX, ATSP-7041 that reactivates p53-dependent pathway in multiple cancer cell lines in vitro and in vivo. This new class of drugs represents a fundamentally new therapeutic approach to modulate signaling pathways to treat human disease.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00021-3
      Issue No: Vol. 49 (2017)
  • Chapter Twenty-Two Cytochrome P450 Enzyme Metabolites in Lead Discovery
           and Development
    • Authors: Sylvie E. Kandel; Larry C. Wienkers; Jed N. Lampe
      Pages: 347 - 359
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Sylvie E. Kandel, Larry C. Wienkers, Jed N. Lampe
      The cytochrome P450 (CYP) enzymes are a versatile superfamily of heme-containing monooxygenases, perhaps best known for their role in the oxidation of xenobiotic compounds. However, due to their unique oxidative chemistry, CYPs are also important in natural product drug discovery and in the generation of active metabolites with unique therapeutic properties. New tools for the analysis and production of CYP metabolites, including microscale analytical technologies and combinatorial biosynthesis, are providing medicinal chemists with the opportunity to use CYPs as a novel platform for lead discovery and development. In this review, we highlight some of the recent examples of drug leads identified from CYP metabolites and the exciting possibilities of using CYPs as catalysts for future drug discovery.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00022-5
      Issue No: Vol. 49 (2017)
  • Chapter Twenty-Three Case History
    • Authors: William N. Washburn
      Pages: 363 - 382
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): William N. Washburn
      Sodium–glucose cotransporter 2 inhibitors are a novel class of agents for the treatment of type 2 diabetes mellitus. These agents reduce hyperglycemia via a paradigm-breaking insulin-independent mechanism entailing promotion of glucosuria by inhibiting renal recovery of glucose. This chapter relates the salient events that enabled the evolution from hydrolytically unstable phenolic O-glucosides beginning with natural product phlorizin to glucosidase impervious C-aryl glucosides that culminated with the identification of dapagliflozin. The synthesis and pharmacology of dapagliflozin is briefly summarized. Disclosure of the synthesis and properties of these novel agents prompted the pharmaceutical industry to initiate more than 20 programs seeking C-glucosides that would emulate dapagliflozin.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00023-7
      Issue No: Vol. 49 (2017)
  • Chapter Twenty-Four Case History
    • Authors: Sabine Hadida; Frederick Van Goor; Kirk Dinehart; Adam R. Looker; Peter Mueller; Peter D.J. Grootenhuis
      Pages: 383 - 398
      Abstract: Publication date: 2014
      Source:Annual Reports in Medicinal Chemistry, Volume 49
      Author(s): Sabine Hadida, Frederick Van Goor, Kirk Dinehart, Adam R. Looker, Peter Mueller, Peter D.J. Grootenhuis
      Cystic fibrosis (CF) is caused by mutations in the CFTR gene of an epithelial ion channel, the CF transmembrane conductance regulator (CFTR). We initiated efforts to discover potentiators of mutated CFTR. Potentiators are small molecules that increase the flow of ions through activated CFTR in the cell membrane. In-house HTS campaigns led to the identification of multiple hits. Extensive medicinal chemistry efforts driven by phenotypic assays led to the discovery of VX-770 (ivacaftor). VX-770 was found to be a potent, selective, orally bioavailable potentiator of G551D-CFTR, displaying excellent pharmacokinetic and safety profiles in rodents and nonrodents. Due to poor aqueous solubility, extensive formulation efforts were required and resulted in a spray-dried dispersion of VX-770 suitable for clinical development. After successful clinical trials, ivacaftor was approved by the FDA in 2012 for the treatment of people with CF who have a G551D mutation in the CFTR gene.

      PubDate: 2017-12-02T07:00:46Z
      DOI: 10.1016/b978-0-12-800167-7.00024-9
      Issue No: Vol. 49 (2017)
  • Series Page
    • Abstract: Publication date: 2017
      Source:Annual Reports in Medicinal Chemistry, Volume 50

      PubDate: 2017-11-21T07:32:13Z
  • Keyword Index, Volume 50
    • Abstract: Publication date: 2017
      Source:Annual Reports in Medicinal Chemistry, Volume 50

      PubDate: 2017-11-21T07:32:13Z
  • Cumulative Chapter Titles Keyword Index, Volume 1 – 50
    • Abstract: Publication date: 2017
      Source:Annual Reports in Medicinal Chemistry, Volume 50

      PubDate: 2017-11-21T07:32:13Z
  • Cumulative NCE Introduction Index, 1983–2017
    • Abstract: Publication date: 2017
      Source:Annual Reports in Medicinal Chemistry, Volume 50

      PubDate: 2017-11-21T07:32:13Z
  • Cumulative NCE Introduction Index, 1983–2017 (by Indication)
    • Abstract: Publication date: 2017
      Source:Annual Reports in Medicinal Chemistry, Volume 50

      PubDate: 2017-11-21T07:32:13Z
  • From Natural Peptides to Market
    • Authors: Claudio D. Schteingart; Jolene L. Lau
      Abstract: Publication date: Available online 10 November 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Claudio D. Schteingart, Jolene L. Lau
      Taking as examples the peptides approved in the United States, Europe, and Japan up to June 2017, this chapter examines the transformation of natural peptides into safe and efficacious drugs. Although peptides have higher progression rates from drug candidate selection to Phase 2 than small molecules, a few safety issues specific to peptides need to be considered. Because of their hydrophilicity and molecular weight, peptides can only address molecular targets on the surface of cells or in the extracellular fluid. Peptidic agonists generally are based on the structure of the natural peptide, which provide leads with high potency, but typically insufficient selectivity and poor pharmacokinetic properties, which are improved during drug discovery programs. The switch from agonists to antagonists is achieved by judicious changes of structure, exemplified with several peptides on the market. Multiple examples illustrate how the clearance and half-life of a candidate peptide is tailored to the desired dosing interval, which must be appropriate to the severity of the condition treated. This and the physicochemical properties of the peptide dictate in turn the modes and routes of administration of the drug. Scenarios are suggested where the discovery of a peptide-based drug might be preferable to that of a small molecule.

      PubDate: 2017-11-11T11:48:43Z
      DOI: 10.1016/bs.armc.2017.08.003
  • Recent Advances of Microfluidics Technologies in the Field of Medicinal
    • Authors: László Ürge; Jesus Alcazar; Lena Huck; György Dormán
      Abstract: Publication date: Available online 9 November 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): László Ürge, Jesus Alcazar, Lena Huck, György Dormán
      Microfluidics, mesofluidics, and lab-on-a-chip technologies have been extensively researched in the pharma and life science industry over the last two decades, including synthesis of novel compounds and building blocks, medicinal chemistry support, biological screening, DMPK studies, and formulation and manufacturing of APIs and final products. These technologies can provide significant advantages over traditional methods and have the potential to revolutionize certain aspects of pharma R&D. The recent developments on the application of these novel techniques, their penetration in the industry, and their barriers for the further adaptation will be extensively discussed in this overview.

      PubDate: 2017-11-11T11:48:43Z
      DOI: 10.1016/bs.armc.2017.09.001
  • Antibody-Recruiting Small Molecules: Synthetic Constructs as
    • Authors: Patrick J. McEnaney; Christopher G. Parker; Andrew X. Zhang
      Abstract: Publication date: Available online 9 November 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Patrick J. McEnaney, Christopher G. Parker, Andrew X. Zhang
      The ability to harness one's endogenous immune response against a pathogen has significantly advanced the treatment of many serious diseases. While immune-based therapeutic strategies have traditionally been dominated by biologics, recent advances at the interface of organic chemistry and immunology have yielded new classes of small molecules that can direct and regulate immune responses. This chapter focuses on the development and application of one such class of small molecules called antibody-recruiting small molecules (ARMs) for the treatment of cancer and infectious diseases. ARMs are bifunctional small molecules that simultaneously bind to a pathogen-associated cell surface biomarker and endogenous antibodies, forming a ternary complex. Formation of the ternary complex then directs antibody dependent, immune effector functions, resulting in targeted cytotoxicity. Here, we present an overview of the conception and evolution of ARMs, including key case studies highlighting their in vitro and in vivo efficacies, as well as some key challenges and perspectives of this area of research in the context of drug discovery and clinical application.

      PubDate: 2017-11-11T11:48:43Z
      DOI: 10.1016/bs.armc.2017.08.008
  • A Decade of Deuteration in Medicinal Chemistry
    • Authors: Julie F. Liu; Scott L. Harbeson; Christopher L. Brummel; Roger Tung; Robert Silverman; Dario Doller
      Abstract: Publication date: Available online 9 November 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Julie F. Liu, Scott L. Harbeson, Christopher L. Brummel, Roger Tung, Robert Silverman, Dario Doller
      The use of deuterium substitution in an effort to produce kinetic isotope effects (KIEs) that favorably alter pharmacokinetics and metabolism in drug discovery has accelerated in the last decade. While the effects of deuteration remain highly experimentally determined and are unpredictable, an increasing number of deuterated drug candidates have progressed from early patent filings to successful proof-of-concept human studies, including the first FDA-approved deuterated drug. The scope of use of KIEs in drug design has expanded, and now deuteration of drug candidates and tool compounds, including imaging ligands, has become a welcome instrument in the arsenal of medicinal chemists. It is expected that experimentation with strategic introduction of deuterium into the structures of organic compounds will continue to increase and may enable the future development of a variety of novel drugs and chemical tools. In this chapter an update on the topic of deuterium substitution in medicinal chemistry will be provided, focusing on the diversity of ways in which medicinal chemists are using deuteration in their efforts to deliver better drugs.

      PubDate: 2017-11-11T11:48:43Z
      DOI: 10.1016/bs.armc.2017.08.010
  • DNA-Encoded Library Technology: A Brief Guide to Its Evolution and Impact
           on Drug Discovery
    • Authors: Robert A. Goodnow; Christopher P. Davie
      Abstract: Publication date: Available online 6 November 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Robert A. Goodnow, Christopher P. Davie
      In the 25 years since the first publication of the concept of encoded combinatorial library synthesis with sequences of DNA, DNA-encoded library technology (DELT) has become a widely accepted method for hit finding along with high-throughput screening. This method has been shown to be useful by the numerous, valuable hits that have been published as well as by the announcement of several drug development candidates that originated from DELT hits. Multiple methods exist for directing and encoding library synthesis, demonstrating the robust nature of this informational and functional platform. In its current, commonly practiced format, this method is in theory readily applicable to any hit finding problem for soluble protein targets. The robust nature of DNA binding and recognition properties is part of the continuous evolution of DNA-encoded and DNA-directed methods.

      PubDate: 2017-11-11T11:48:43Z
      DOI: 10.1016/bs.armc.2017.09.002
  • Free Energy Calculation Guided Virtual Screening of Synthetically Feasible
           Ligand R-Group and Scaffold Modifications: An Emerging Paradigm for Lead
    • Authors: Robert Abel; Sathesh Bhat
      Abstract: Publication date: Available online 26 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Robert Abel, Sathesh Bhat
      Virtual screening of small-molecule collections has become a widespread practice both in academic laboratories and in pharmaceutical companies to rapidly and inexpensively identify small molecules which bind to the intended target with sufficient affinity to facilitate initiation of a drug discovery project. However, this approach of computationally evaluating very large numbers of small molecules, and then selecting a small subset of these for additional experimental prosecution is seldom employed in the lead optimization phase of drug discovery project. Recent work enabling programmatic enumeration of the synthetically tractable idea space around the most promising lead molecules when appropriately combined with high-accuracy protein–ligand binding free energy calculations appears poised to allow this emerging paradigm to make great contributions to lead optimization.

      PubDate: 2017-11-05T10:52:00Z
      DOI: 10.1016/bs.armc.2017.08.007
  • Kinase-Centric Computational Drug Development
    • Authors: Albert J. Kooistra; Andrea Volkamer
      Abstract: Publication date: Available online 15 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Albert J. Kooistra, Andrea Volkamer
      Kinases are among the most studied drug targets in industry and academia, due to their involvement in a majority of cellular processes and, upon dysregulation, in a variety of diseases including cancer, inflammation, and autoimmune disorders. The high interest in this druggable protein family triggered the generation of a large pool of data comprising sequence, structure, bioactivity, and mutation data. Together with this continuously growing amount of available data, comes the need as well as the opportunity to organize, analyze, and utilize this data in order to aid the design of novel, active, and potentially selective kinase inhibitors. In this chapter, we provide a comprehensive overview of kinase-centric data resources and tools that can be utilized for computationally driven kinase research. The contents of all resources are summarized, and all platforms focused on human kinases are discussed in more detail. Furthermore, practical applications from literature and illustrative examples showcasing the aforementioned sources and tools are presented. These applications utilize sequence, structure, and bioactivity data and range from single structure analysis, sequence comparisons, binding site predictions, druggability predictions, and protein–ligand interaction fingerprinting to activity predictions using machine learning methods. Finally, a perspective is given on the unmet needs, potential pitfalls, and current developments in kinase drug design.

      PubDate: 2017-11-05T10:52:00Z
      DOI: 10.1016/bs.armc.2017.08.001
  • High-Throughput Screening
    • Authors: Mary Jo Wildey; Anders Haunso; Matthew Tudor; Maria Webb; Jonathan H. Connick
      Abstract: Publication date: Available online 15 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Mary Jo Wildey, Anders Haunso, Matthew Tudor, Maria Webb, Jonathan H. Connick
      This review provides an overview of the science of high-throughput screening (HTS) within the pharmaceutical industry and the greater drug discovery community. From its origins in the early 1990s to the current state of the art, key aspects of the process are introduced and described in increasing levels of detail. Examples of technologies employed in the automation of HTS are provided, together with an evaluation of their applicability and limitations. The various detection modalities typically encountered, and their suitability to high-density screening formats (96, 386, 1536, or 3456 well) are described. The increasing importance of informatics in screen design, data interpretation, quality control, and its contribution to the development of future HTS strategies is introduced. Current and future trends of how HTS is employed to meet the changing needs for new drug discovery are explored, including the parallel use of complementary screening modalities to sample diverse chemical matter and identify the best starting points for drug discovery programs.

      PubDate: 2017-11-05T10:52:00Z
      DOI: 10.1016/bs.armc.2017.08.004
  • CRISPR–Cas9 for Drug Discovery in Oncology
    • Authors: Sylvie M. Guichard
      Abstract: Publication date: Available online 13 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Sylvie M. Guichard
      Drug discovery is a complex enterprise bringing together a variety of skills and techniques. Oncology drug discovery has taken advantage of cancer genetics to identify drug molecules tailored to specific subset of tumors which has proven highly beneficial to patients. Modifying the genome to understand better cancer genetics has been instrumental in this process. CRISPR–Cas9 is a new programmable gene-editing tool which expand dramatically the scope of genetic manipulation to decipher cancer biology. CRISPR–Cas9 has taken drug discovery by storm and many facets of drug discovery could benefit from this technology. This chapter will briefly touch on the mechanism of genome editing and the growing number of modified Cas9 enzymes before presenting how CRISPR–Cas9 is impacting different aspects of drug discovery namely target identification, validation and deconvolution, reagent generation and drug synthesis, assessment of drug sensitivity and drug resistance, as well as drug disposition and toxicology.

      PubDate: 2017-10-14T14:31:54Z
      DOI: 10.1016/bs.armc.2017.08.006
  • Fragment-Based Lead Discovery
    • Authors: Ben J. Davis; Stephen D. Roughley
      Abstract: Publication date: Available online 12 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Ben J. Davis, Stephen D. Roughley
      Since its inception in the late 1990s, fragment-based lead discovery (FBLD) has developed into a robust and generic approach for drug discovery. Two clinically approved drugs have been developed using the FBLD approach, and at least 30 FBLD-derived compounds are in various stages of clinical development. Based on the principle of the identification of small (and hence typically low affinity) ligands which make well-defined interactions with the receptor, and the evolution of these initial fragment hits into larger, more potent ligands that maintain these key interactions, FBLD has proven to be a reliable technique which is applicable to wide range of targets. In this chapter, we will discuss the philosophy and rationale underpinning the FBLD approach, theoretical and practical considerations of fragment library design, fragment screening and characterization, and the evolution of initial low molecular weight fragment hits into larger, potent molecules suitable for lead optimization and preclinical development. We will also discuss informative case histories, showing the challenges, pitfalls, and successful approaches, which have been applied to a number of therapeutically relevant targets.

      PubDate: 2017-10-14T14:31:54Z
      DOI: 10.1016/bs.armc.2017.07.002
  • Targeted Protein Degradation
    • Authors: Nello Mainolfi; Tim Rasmusson
      Abstract: Publication date: Available online 9 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Nello Mainolfi, Tim Rasmusson
      Targeted protein degradation is arguably one of the most exciting novel therapeutic modalities in drug discovery. Moving away from occupancy-based pharmacology models and their challenges with selectivity, on/off target toxicities, and PK–PD limitations, it provides a novel and orthogonal therapeutic paradigm. The ability to induce degradation using a small molecule without the need to inhibit a specific protein function allows access to unexplored new areas of biology and targeting historically intractable protein targets. This chapter reviews the field especially focusing on heterobifunctional molecule-driven target degradation and highlights great progress but also gaps needed to be filled as the field moves toward clinical validation.

      PubDate: 2017-10-14T14:31:54Z
      DOI: 10.1016/bs.armc.2017.08.005
  • Platform Technologies in Drug Discovery and Target Validation
    • Authors: Amit Kumar; Jason White James Christie Nazzareno Dimasi Changshou Gao
      Abstract: Publication date: Available online 4 October 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Amit Kumar, Jason White, R. James Christie, Nazzareno Dimasi, Changshou Gao
      Antibody–drug conjugates (ADCs) are designed with the purpose of delivering small-molecule cytotoxic drug to antigen-expressing tumor cells by harnessing the specificity, biodistribution, and pharmacokinetics of antibodies. ADCs are comprised of three components: the antibody, the linker, and the cytotoxic agent. To achieve the desired goal of targeted therapy with anticipated efficacy and safety profiles, each ADC component must be carefully selected and optimized. In this chapter, we introduce the main concepts and technologies associated with clinical development of ADCs. Considerations regarding ADC production such as drug–antibody conjugation, linker technologies, and cytotoxic agents are discussed. In addition, we describe analytical methods to characterize ADC products for assessment of drug content and purity. Finally, mechanistic aspects ADCs in vivo and the underlying key factors effecting on- and off-target toxicities are introduced.

      PubDate: 2017-10-08T21:21:56Z
  • The Chemistry of Oligonucleotide Delivery
    • Authors: David B. Rozema
      Abstract: Publication date: Available online 13 September 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): David B. Rozema
      The field of oligonucleotide-based therapeutics has advanced through decades of research and development to identify diverse structures and mechanisms of action with the aim of using nucleic acids as drugs. Despite this diversity, there are common characteristics that all oligonucleotides require to be functional drugs: potency, stability against nucleases, and access to sites of activity. The aim of this review is to introduce the different types of nucleic acid therapeutics and the strategies for attaining the “drug-like” attributes required of membrane-impermeable nucleic acids.

      PubDate: 2017-09-17T18:37:40Z
      DOI: 10.1016/bs.armc.2017.07.003
  • Phenotypic Screening
    • Authors: Alleyn T. Plowright; Lauren Drowley
      Abstract: Publication date: Available online 4 September 2017
      Source:Annual Reports in Medicinal Chemistry
      Author(s): Alleyn T. Plowright, Lauren Drowley
      Phenotypic screening is now reestablished in academia and industry as an approach to discover novel drug targets, pathways, and high-quality hit and lead molecules. The increased access to patient-derived cells or tissues and developments in induced pluripotent stem cell technology coupled to more complex cellular systems such as three-dimensional cultures or organs on a chip is providing opportunities for more disease-relevant screens. Different modalities are available to screen including small molecules, siRNA, antibodies, and CRISPR libraries, and each offers a range of advantages and disadvantages. The size of the phenotypic screen can range from high-throughput screens to more hypothesis-based selections including biological measures of diversity. New approaches are now appearing based on the principles of fragment-based screening. One of the major challenges in phenotypic screening is the deconvolution of the biological target(s) of the hit molecules, but a range of methods based on computational techniques utilizing different sources of data can infer the possible targets to generate initial target hypotheses which can be tested. Even in the absence of biological target information, if the phenotypic assay is sufficiently robust, compounds can be optimized into lead molecules and even clinical candidates. The application of cross-disciplinary phenotypic discovery to probe emerging biology is a powerful and exciting approach to discover new biological targets and molecules and, as highlighted in this chapter, is making a significant impact on drug discovery and ultimately delivering transformative medicines to impact the lives of patients.

      PubDate: 2017-09-06T17:00:52Z
      DOI: 10.1016/bs.armc.2017.07.001
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