Title Case studies in modern drug discovery and development / edited by Xianhai Huang, Robert G. Aslanian

Published Oxford : Wiley-Blackwell ; Hoboken, N.J. : John Wiley & Sons, 2012

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Description 1 online resource (xviii, 451 pages) : illustrations Contents 880-01 Introduction: drug discovery in difficult times / Malcom MacCoss -- Discovery and development of the DPP-4 inhibitor JANUVIA (Sita-gliptin) / Emma R. Parmee [and others] -- Olmesartan medoxomil, an angiotensin II receptor blocker / Hiroaki Yanagisawa, Hiroyuki Koike, and Shini-chiro Miura -- Discovery of heterocyclic phosphonic acids as novel AMP mimics that are potent and selective fructose-1,6-bisphosphatase inhibitors and elicit potent glucose-lowering effects in diabetic animals and humans / Qun Dang and Mark D. Erion -- Setting the paradigm of targeted drugs for the treatment of cancer : Imatinib and Nilotinib, therapies for chronic myelogenous leukemia / Paul W. Manley and Jürg Zimmermann -- Amrubicin, a completely synthetic 9-aminoanthracycline for extensive-disease small-cell lung cancer / Mitsuharu Hanada -- The discovery of dual IGF-1R and IR inhibitor FQIT for the treatment of cancer / Meizhong Jin, Elizabeth Buck, and Mark J. Mulvihill -- Discovery and development of Montelukast (Singulair) / Robert N. Young -- Discovery and development of Maraviroc, a CCR5 antagonist for the treatment of HIV infection / Patrick Dorr, Blanda Stammen, Elna van der Ryst -- Discovery of antimalarial drug Artemisinin and beyond / Weiwei Mao, Yu Zhang, and Ao Zhang -- Discovery and process development of MK-4965, a potent nonnucleoside reverse transcriptase inhibitor / Yong-Li Zhong, Thomas J. Tucker, and Jingjun Yin -- Discovery of Boceprevir and Narlaprevir : the first and second generation of HCV NS3 protease inhibitors / Kevin X. Chen and F. George Njoroge -- The discovery of Samsca (Tolvaptan) : the first oral nonpeptide vasopressin receptor antagonist / Kazumi Kondo and Yoshitaka Yamamura -- SILODOSIN (Urief, Rapaflo, Thrupas, Urorec, Silodix) : a selective à1A adrenoceptor antagonist for the treatment of benign prostatic hyperplasia / Masaki Yoshida [and others] -- Raloxifene : a selective estrogen receptor modulator (SERM) / Jeffrey A. Dodge and Henry U. Bryant 880-01/(S Contents note continued: 10.4. Synthesis of Artemisinin -- 10.4.1. Synthesis of Artemisinin using Photooxidation of Cyclic or Acyclic Enol Ether as the Key Step -- 10.4.2. Synthesis of Artemisinin by Photooxidation of Dihydroarteannuic Acid -- 10.4.3. Synthesis of Artemisinin by Ozonolysis of a Vinylsilane Intermediate -- 10.5. SAR Studies of Structural Derivatives of Artemisinin: The Discovery of Artemether -- 10.5.1. C-10-Derived Artemisinin Analogs -- 10.5.2. C-9 and C-9,10 Double Substituted Analogs -- 10.5.3. C-3 Substituted Analogs -- 10.5.4. C-6 or C-7 Substituted Derivatives -- 10.5.5. C-11-Substituted Analogs -- 10.6. Development of Artemether -- 10.6.1. Profile and Synthesis of Artemether -- 10.6.2. Clinical Studies Aspects of Artemether -- 10.7. Conclusion and Perspective -- Acknowledgment -- References -- ch. 11 Discovery And Process Development Of MK-4965, A Potent Nonnucleoside Reverse Transcriptase Inhibitor / Jingjun Yin -- 11.1. Introduction -- 11.2. Discovery of MK-4965 -- 11.2.1. Background Information -- 11.2.2. SAR Studies Leading to the Discovery of MK-4965 -- 11.3. Preclinical and Clinical Studies of MK-4965 (19) -- 11.4. Summary of Back-Up SAR Studies of MK-4965 Series -- 11.5. Process Development of MK-4965 (19) -- 11.5.1. Medicinal Chemistry Route -- 11.5.2. Process Development -- 11.6. Conclusion -- 11.6.1. Lessons Learned from the Medicinal Chemistry Effort of MK-4965 Discovery -- 11.6.2. Summary and Lessons Learned from the Process Development of MK-4965 -- Acknowledgments -- References -- ch. 12 Discovery Of Boceprevir And Narlaprevir: The First And Second Generation Of HCV NS3 Protease Inhibitors / F. George Njoroge -- 12.1. Introduction -- 12.2. HCV NS3 Protease Inhibitors -- 12.3. Research Operation Plan and Biological Assays -- 12.3.1. Research Operation Plan -- 12.3.2. Enzyme Assay -- 12.3.3. Replicon Assay -- 12.3.4. Measure of Selectivity -- 12.4. Discovery of Boceprevir -- 12.4.1. Initial Lead Generation Through Structure-Based Drug Design -- 12.4.2. SAR Studies Focusing on Truncation, Depeptization, and Macrocyclisation -- 12.4.3. Individual Amino Acid Residue Modifications -- 12.4.4. Correlations Between P1, P3, and P3 Capping: The Identification of Boceprevir -- 12.5. Profile of Boceprevir -- 12.5.1. In Vitro Characterization of Boceprevir -- 12.5.2. Pharmacokinetics of Boceprevir -- 12.5.3. Interaction of Boceprevir with NS3 Protease -- 12.6. Clinical Development and Approval of Boceprevir -- 12.7. Synthesis of Boceprevir -- 12.8. Discovery of Narlaprevir -- 12.8.1. Criteria for the Back-up Program of Boceprevir -- 12.8.2. SAR Studies -- 12.8.3. Profile of Narlaprevir -- 12.8.4. Clinical Development Aspects of Narlaprevir -- 12.8.5. Synthesis of Narlaprevir -- 12.9. Summary -- References -- ch. 13 Discovery Of Samsca® (Tolvaptan): The First Oral Nonpeptide Vasopressin Receptor Antagonist / Yoshitaka Yamamura -- 13.1. Background Information about the Disease -- 13.2. Biological Rational -- 13.3. Lead Generation Strategies: The Discovery of Mozavaptan -- 13.4. Lead Optimization: From Mozavaptan to Tolvaptan -- 13.5. Pharmacological Profiles of Tolvaptan -- 13.5.1. Antagonistic Affinities of Tolvaptan for AVP Receptors -- 13.5.2. Aquaretic Effect Following a Single Dose in Conscious Rats -- 13.6. Drug Development -- 13.6.1. Synthetic Route of Discovery and Commercial Synthesis [10a] -- 13.6.2. Nonclinical Toxicology -- 13.6.3. Clinical Studies -- 13.7. Summary Focusing on Lessons Learned -- Acknowledgments -- References -- ch. 14 Silodosin (Urief®, Rapaflo®, Thrupas®, Urorec®, Silodix[™]): A Selective α1A Adrenoceptor Antagonist For The Treatment Of Benign Prostatic Hyperplasia / Junzo Kudoh -- 14.1. Background Information -- 14.1.1. Benign Prostatic Hyperplasia -- 14.1.2. α1-Adrenergic Receptors -- 14.2. Discovery of Silodosin -- 14.2.1. Medicinal Chemistry -- 14.2.2. Synthesis of Silodosin (Discovery Route) -- 14.2.3. Receptor Binding Studies -- 14.3. Pharmacology of Silodosin -- 14.3.1. Action Against Noradrenalin-Induced Contraction of Lower Urinary Tract Tissue -- 14.3.2. Actions Against Phenylephrine-Induced Increase in Intraurethral Pressure and Blood Pressure -- 14.3.3. Actions Against Intraurethral Pressure Increased by Stimulating Hypogastric Nerve and Blood Pressure in Dogs with Benign Prostatic Hyperplasia -- 14.3.4. Safety Pharmacology -- 14.4. Metabolism of Silodosin -- 14.5. Pharmacokinetics of Silodosin -- 14.5.1. Absorption -- 14.5.2. Organ Distribution -- 14.5.3. Excretion -- 14.6. Toxicology of Silodosin -- 14.7. Clinical Trials -- 14.7.1. Phase I Studies -- 14.7.2. Phase III Randomized, Placebo-Controlled, Double-Blind Study -- 14.7.3. Long-Term Administration Study -- 14.8. Summary: Key Lessons Learned -- References -- ch. 15 Raloxifene: A Selective Estrogen Receptor Modulator (Serm) / Henry U. Bryant -- 15.1. Introduction: SERMs -- 15.2. Benzothiophene Scaffold: A New Class of SERMs -- 15.3. Assays for Biological Evaluation of Tissue Selectivity -- 15.4. Benzothiophene Structure Activity -- 15.5. Synthesis of Raloxifene -- 15.6. SERM Mechanism -- 15.7. Raloxifene Pharmacology -- 15.7.1. Skeletal System -- 15.7.2. Reproductive System---Uterus -- 15.7.3. Reproductive System---Mammary -- 15.7.4. General Safety Profile and Other Pharmacological Considerations -- 15.8. Summary -- References Summary "Written by international experts in drug discovery and development, this book sets forth carefully researched and analyzed case studies of both successful and failed drug discovery and development efforts, enabling medicinal chemists and pharmaceutical scientists to learn from actual examples. Each case study focuses on a particular drug and therapeutic target, guiding readers through the drug discovery and development process, including drug design rationale, structure-activity relationships, pharmacology, drug metabolism, biology, and clinical studies."-- Provided by publisher Bibliography Includes bibliographical references and index Notes Print version record Subject Drug development -- Case studies Drugs -- Design -- Case studies Pharmaceutical chemistry -- Case studies Pharmaceutical chemistry. Pharmacology. Chemistry. Life sciences. Physical sciences. Chemistry, Pharmaceutical Investigative Techniques Evaluation Studies as Topic Pharmacology Chemistry Analytical, Diagnostic and Therapeutic Techniques and Equipment Biological Science Disciplines Natural Science Disciplines Disciplines and Occupations Drug Discovery Drug Evaluation pharmacology. chemistry. biological sciences. physical sciences. MEDICAL -- Drug Guides. MEDICAL -- Nursing -- Pharmacology. MEDICAL -- Pharmacology. MEDICAL -- Pharmacy. Physical sciences Pharmacology Life sciences Chemistry Drug development Drugs -- Design Pharmaceutical chemistry Genre/Form Case studies Form Electronic book Author Huang, Xianhai. Aslanian, Robert G. ISBN 9781118219683 1118219686 9781118219706 1118219708 9781118219676 1118219678

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