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Case studies in modern drug discovery and development /
"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....
| Clasificación: | Libro Electrónico |
|---|---|
| Otros Autores: | , |
| Formato: | Electrónico eBook |
| Idioma: | Inglés |
| Publicado: |
Oxford : Hoboken, N.J. :
Wiley-Blackwell ; John Wiley & Sons,
2012.
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| Temas: | |
| Acceso en línea: | Texto completo |
MARC
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| 037 | |a 362083 |b MIL | ||
| 037 | |a 10.1002/9781118219683 |b Wiley InterScience |n http://www3.interscience.wiley.com | ||
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| 049 | |a UAMI | ||
| 245 | 0 | 0 | |a Case studies in modern drug discovery and development / |c edited by Xianhai Huang, Robert G. Aslanian. |
| 260 | |a Oxford : |b Wiley-Blackwell ; |a Hoboken, N.J. : |b John Wiley & Sons, |c 2012. | ||
| 300 | |a 1 online resource (xviii, 451 pages) : |b illustrations | ||
| 336 | |a text |b txt |2 rdacontent | ||
| 337 | |a computer |b c |2 rdamedia | ||
| 338 | |a online resource |b cr |2 rdacarrier | ||
| 504 | |a Includes bibliographical references and index. | ||
| 505 | 0 | |6 880-01 |a 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. | |
| 520 | |a "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."-- |c Provided by publisher. | ||
| 588 | 0 | |a Print version record. | |
| 590 | |a ProQuest Ebook Central |b Ebook Central Academic Complete | ||
| 650 | 0 | |a Drug development |v Case studies. | |
| 650 | 0 | |a Drugs |x Design |v Case studies. | |
| 650 | 0 | |a Pharmaceutical chemistry |v Case studies. | |
| 650 | 0 | |a Pharmaceutical chemistry. | |
| 650 | 0 | |a Pharmacology. | |
| 650 | 0 | |a Chemistry. | |
| 650 | 0 | |a Life sciences. | |
| 650 | 0 | |a Physical sciences. | |
| 650 | 2 | |a Chemistry, Pharmaceutical | |
| 650 | 2 | |a Investigative Techniques | |
| 650 | 2 | |a Evaluation Studies as Topic | |
| 650 | 2 | |a Pharmacology | |
| 650 | 2 | |a Chemistry | |
| 650 | 2 | |a Analytical, Diagnostic and Therapeutic Techniques and Equipment | |
| 650 | 2 | |a Biological Science Disciplines | |
| 650 | 2 | |a Natural Science Disciplines | |
| 650 | 2 | |a Disciplines and Occupations | |
| 650 | 2 | |a Drug Discovery | |
| 650 | 2 | |a Drug Evaluation | |
| 650 | 4 | |a Health & Biological Sciences. | |
| 650 | 4 | |a Pharmacy, Therapeutics, & Pharmacology. | |
| 650 | 6 | |a Médicaments |x Développement |v Études de cas. | |
| 650 | 6 | |a Médicaments |x Conception |v Études de cas. | |
| 650 | 6 | |a Chimie pharmaceutique |v Études de cas. | |
| 650 | 6 | |a Chimie pharmaceutique. | |
| 650 | 6 | |a Pharmacologie. | |
| 650 | 6 | |a Chimie. | |
| 650 | 6 | |a Sciences de la vie. | |
| 650 | 6 | |a Sciences physiques. | |
| 650 | 7 | |a pharmacology. |2 aat | |
| 650 | 7 | |a chemistry. |2 aat | |
| 650 | 7 | |a biological sciences. |2 aat | |
| 650 | 7 | |a physical sciences. |2 aat | |
| 650 | 7 | |a MEDICAL |x Drug Guides. |2 bisacsh | |
| 650 | 7 | |a MEDICAL |x Nursing |x Pharmacology. |2 bisacsh | |
| 650 | 7 | |a MEDICAL |x Pharmacology. |2 bisacsh | |
| 650 | 7 | |a MEDICAL |x Pharmacy. |2 bisacsh | |
| 650 | 7 | |a Physical sciences |2 fast | |
| 650 | 7 | |a Pharmacology |2 fast | |
| 650 | 7 | |a Life sciences |2 fast | |
| 650 | 7 | |a Chemistry |2 fast | |
| 650 | 7 | |a Drug development |2 fast | |
| 650 | 7 | |a Drugs |x Design |2 fast | |
| 650 | 7 | |a Pharmaceutical chemistry |2 fast | |
| 655 | 7 | |a Case studies |2 fast | |
| 700 | 1 | |a Huang, Xianhai. | |
| 700 | 1 | |a Aslanian, Robert G. | |
| 758 | |i has work: |a Case studies in modern drug discovery and development (Text) |1 https://id.oclc.org/worldcat/entity/E39PCXvhwxqvvf8ydyGVPdtFrq |4 https://id.oclc.org/worldcat/ontology/hasWork | ||
| 776 | 0 | 8 | |i Print version: |t Case studies in modern drug discovery and development. |d Hoboken : John Wiley & Sons, ©2012 |z 9786613620835 |z 9780470601815 |w (OCoLC)755056546 |
| 856 | 4 | 0 | |u https://ebookcentral.uam.elogim.com/lib/uam-ebooks/detail.action?docID=822083 |z Texto completo |
| 880 | 0 | 0 | |6 505-00/(S |g Machine generated contents note: |g ch. 1 |t Introduction: Drug Discovery In Difficult Times / |r Malcolm MacCoss -- |g ch. 2 |t Discovery And Development Of The DPP-4 Inhibitor Januvia[™] (Sita-Gliptin) / |r Lawrence A. Rosen -- |g 2.1. |t Introduction -- |g 2.2. |t DPP-4 Inhibition as a Therapy for Type 2 Diabetes: Identification of Key Determinants for Efficacy and Safety -- |g 2.2.1. |t Incretin-Based Therapy for T2DM -- |g 2.2.2. |t Biological Rationale: DPP-4 is a Key Regulator of Incretin Activity -- |g 2.2.3. |t Injectable GLP-1 Mimetics for the Treatment of T2DM -- |g 2.2.4. |t DPP-4 Inhibition as Oral Incretin-Based Therapy for T2DM -- |g 2.2.5. |t Investigation of DPP-4 Biology: Identification of Candidate Substrates -- |g 2.2.6. |t Preclinical Toxicities of In-Licensed DPP-4 Inhibitors -- |g 2.2.7. |t Correlation of Preclinical Toxicity with Off-Target Inhibition of Pro-Specific Dipeptidase Activity -- |g 2.2.8. |t Identification of Pro-Specific Dipeptidases Differentially Inhibited by the Probiodrug Compounds -- |g 2.2.9. |t Highly Selective DPP-4 Inhibitor is Safe and Well Tolerated in Preclinical Species -- |g 2.2.10. |t Highly Selective DPP-4 Inhibitor Does Not Inhibit T-Cell Proliferation in vitro -- |g 2.2.11. |t DPP-4 Inhibitor Selectivity as a Key Parameter for Drug Development -- |g 2.3. |t Medicinal Chemistry Program -- |g 2.3.1. |t Lead Generation Approaches -- |g 2.3.2. |t Cyclohexyl Glycine α-Amino Acid Series of DPP-4 Inhibitors -- |g 2.3.3. |t Improving Selectivity of the α-Amino Acid Series -- |g 2.3.4. |t Identification and Optimization of the β-Amino Acid Series -- |g 2.4. |t Synthetic and Manufacturing Routes to Sitagliptin -- |g 2.4.1. |t Medicinal Chemistry Route to Sitagliptin and Early Modifications -- |g 2.4.2. |t Asymmetric Hydrogenation Manufacturing Route to Sitagliptin -- |g 2.4.3. |t "Greener" Manufacturing Route to Sitagliptin Employing Biocatalytic Transamination -- |g 2.5. |t Drug Product Development -- |g 2.5.1. |t Overview -- |g 2.5.2. |t Composition Development -- |g 2.5.3. |t Manufacturing Process Development -- |g 2.6. |t Clinical Studies -- |g 2.6.1. |t Preclinical PD Studies and Early Clinical Development of Sitagliptin -- |g 2.6.2. |t Summary of Phase II/III Clinical Trials -- |g 2.7. |t Summary -- |t References -- |g ch. 3 |t Olmesartan Medoxomil: An Angiotensin II Receptor Blocker / |r Shin-ichiro Miura -- |g 3.1. |t Background -- |g 3.1.1. |t Introduction -- |g 3.1.2. |t Prototype of Orally Active ARBs -- |g 3.2. |t Discovery of Olmesartan Medoxomil (Benicar) -- |g 3.2.1. |t Lead Generation -- |g 3.2.2. |t Lead Optimization -- |g 3.3. |t Characteristics of Olmesartan -- |g 3.4. |t Binding Sites of Omlersartan to the AT1 Receptor and Its Inverse Agonoist Activity -- |g 3.4.1. |t Binding Sites of Olmesartan to the AT1 Receptor -- |g 3.4.2. |t Inverse Agonist Activity of Olmesartan -- |g 3.4.3. |t Molecular Model of the Interaction between Olmesartan and the AT1 Receptor -- |g 3.5. |t Practical Preparation of Olmesartan Medoxomil -- |g 3.6. |t Preclinical Studies -- |g 3.6.1. |t AT1 Receptor Blocking Action -- |g 3.6.2. |t Inhibition of Ang II-Induced Vascular Contraction -- |g 3.6.3. |t Inhibition of the Pressor Response to Ang II -- |g 3.6.4. |t Blood Pressure Lowering Effects -- |g 3.6.5. |t Organ Protection -- |g 3.7. |t Clinical Studies -- |g 3.7.1. |t Antihypertensive Efficacy and Safety -- |g 3.7.2. |t Organ Protection -- |g 3.8. |t Conclusion -- |t References -- |g ch. 4 |t 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 / |r Mark D. Erion -- |g 4.1. |t Introduction -- |g 4.2. |t Discovery of MB06322 -- |g 4.2.1. |t Research Operation Plan -- |g 4.2.2. |t Discovery of Nonnucleotide AMP Mimics as FBPase Inhibitors -- |g 4.2.3. |t Discovery of Benzimidazole Phosphonic Acids as FBPase Inhibitors -- |g 4.2.4. |t Discovery of Thiazole Phosphonic Acids as Potent and Selective FBPase Inhibitors -- |g 4.2.5. |t Discovery of MB06322 Through Prodrug Strategy -- |g 4.3. |t Pharmacokinetic Studies of MB06322 -- |g 4.4. |t Synthetic Routes to MB06322 -- |g 4.5. |t Clinical Studies of MB06322 -- |g 4.5.1. |t Efficacy Study of Thiazole 12.6 in Rodent Models of T2DM -- |g 4.5.2. |t Phase I/II Clinical Studies -- |g 4.6. |t Summary -- |t References -- |g ch. 5 |t Setting The Paradigm Of Targeted Drugs For The Treatment Of Cancer: Imatinib And Nilotinib, Therapies For Chronic Myelogenous Leukemia / |r Jurg Zimmermann -- |g 5.1. |t Introduction -- |g 5.2. |t Chronic Myelogenous Leukemia (CML) and Early Treatment of the Disease -- |g 5.3. |t Imatinib: A Treatment for Chronic Myelogenous Leukemia (CML) -- |g 5.4. |t Need for New Inhibitorts of BCR-ABL1 and Development of Nilotinib -- |g 5.5. |t Conclusion -- |t References -- |g ch. 6 |t Amrubicin, A Completely Synthetic 9-Aminoanthracycline For Extensive-Disease Small-Cell Lung Cancer / |r Mitsuharu Hanada -- |g 6.1. |t Introduction -- |g 6.2. |t Discovery of Amrubicin: The First Completely Synthetic Anthracycline -- |g 6.3. |t Toxicological Profile of Amrubicin -- |g 6.4. |t DNA Topoisomerase II Inhibition and Apoptosis Induction by Amrubicin -- |g 6.5. |t Amrubicin Metabolism: The Discovery of Amrubicinol -- |g 6.5.1. |t Amrubicinol Functions as an Active Metabolite of Amrubicin -- |g 6.5.2. |t Tumor-Selective Metabolism of Amrubicin to Amrubicinol -- |g 6.6. |t Improved Usage of Amrubicin -- |g 6.7. |t Clinical Trials -- |g 6.7.1. |t Clinical Trials of Amrubicin as First-line Therapy in Patients with ED-SCLC -- |g 6.7.2. |t Clinical Trials of Amrubicin as Second-Line Therapy in Patients with ED-SCLC -- |g 6.8. |t Conclusions -- |t References -- |g ch. 7 |t Discovery Of Dual IGF-1R And IR Inhibitor FQIT For The Treatment Of Cancer / |r Mark J. Mulvihill -- |g 7.1. |t Biological Rational for Targeting the IGF-1R/IR Pathway for Anti-Cancer Therapy -- |g 7.2. |t Discovery Of OSI-906 -- |g 7.2.1. |t Summary of OSI-906 Discovery -- |g 7.2.2. |t OSI-906 Clinical Aspects -- |g 7.3. |t OSI-906 Back Up Efforts -- |g 7.4. |t Discovery Of FQIT -- |g 7.4.1. |t Lead Generation Strategy -- |g 7.4.2. |t Small Molecule Dual IGF-1R/IR Inhibitor Drug Discovery Cascade -- |g 7.4.3. |t Initial Proof-of-Concept Compounds -- |g 7.4.4. |t Synthesis of 5,7-Disubstituted Imidazo[5,1-f][1,2,4] Triazines -- |g 7.4.5. |t Lead Imidazo[5,1-f][1,2,4] Triazine IGF-1R/IR Inhibitors and Emergence of FQIT -- |g 7.5. |t In Vitro Profile of FQIT -- |g 7.5.1. |t Cellular and Antiproliferative Effects as a Result of IGF-1R and IR Inhibition -- |g 7.5.2. |t Cellular Potency in the Presence of Plasma Proteins -- |g 7.5.3. |t In Vitro Metabolism and CYP450 Profile -- |g 7.6. |t Pharmacokinetic Properties of FQIT -- |g 7.6.1. |t Formulation and Salt Study -- |g 7.6.2. |t Pharmacokinetics Following Intravenous Administration -- |g 7.6.3. |t Pharmacokinetics Following Oral Administration -- |g 7.7. |t In Vivo Profile of FQIT -- |g 7.7.1. |t In Vivo Pharmacodynamic and PK/PD Correlation -- |g 7.7.2. |t In Vivo Efficacy -- |g 7.8. |t Safety Assessment and Selectivity Profile of FQIT -- |g 7.8.1. |t Effects on Blood Glucose and Insulin Levels -- |g 7.8.2. |t Oral Glucose Tolerance Test -- |g 7.8.3. |t Ames, Rodent, and Nonrodent Toxicology Studies -- |g 7.8.4. |t Selectivity Profile of FQIT -- |g 7.9. |t Summary -- |t Acknowledgments -- |t References -- |g ch. 8 |t Discovery And Development Of Montelukast (Singulair®) / |r Robert N. Young -- |g 8.1. |t Introduction -- |g 8.2. |t Drug Development Strategies -- |g 8.3. |t LTD4 Antagonist Program -- |g 8.3.1. |t Lead Generation and Optimization -- |g 8.3.2. |t In Vitro and In Vivo Assays -- |g 8.4. |t Discovery of Montelukast (Singulair®) -- |g 8.4.1. |t First-Generation Antagonists (Figure 8.3) -- |g 8.4.2. |t Discovery of MK-571 -- |g 8.4.3. |t Discovery of MK-0679 (29) -- |g 8.4.4. |t Discovery of Montelukast (L-706,631, MK-0476, Singulair®) -- |g 8.5. |t Synthesis of Montelukast -- |g 8.5.1. |t Medicinal Chemistry Synthesis -- |g 8.5.2. |t Process Chemistry Synthesis [104, 105] (Schemes 8.5 and 8.6) -- |g 8.6. |t ADME Studies with MK-0476 (Montelukast) -- |g 8.7. |t Safety Assessment of Montelukast -- |g 8.8. |t Clinical Development of Montelukast -- |g 8.8.1. |t Human Pharmacokinetics, Safety, and Tolerability -- |g 8.8.2. |t Human Pharmacology -- |g 8.8.3. |t Phase 2 Studies in Asthma -- |g 8.8.4. |t Phase 3 Studies in Asthma -- |g 8.8.5. |t Effects of Montelukast on Inflammation -- |g 8.8.6. |t Montelukast and Allergic Rhinitis -- |g 8.9. |t Summary -- |g 8.9.1. |t Impact on Society -- |g 8.9.2. |t Lessons Learned -- |g 8.10. |t Personal Impact -- |t References -- |g ch. |
| 880 | 0 | 0 | |t 9 |t Discovery And Development Of Maraviroc, A CCR5 Antagonist For The Treatment Of HIV Infection / |r Elna van der Ryst -- |g 9.1. |t Background and Rationale -- |g 9.2. |t Discovery of Maraviroc -- |g 9.2.1. |t HTS and Biological Screening to Guide Medicinal Chemistry -- |g 9.2.2. |t Hit Optimization -- |g 9.2.3. |t Overcoming Binding to hERG -- |g 9.3. |t Preclinical Studies -- |g 9.3.1. |t Metabolism and Pharmacokinetic Characteristics of Maraviroc -- |g 9.3.2. |t Maraviroc Preclinical Pharmacology -- |g 9.3.3. |t Preclinical Investigations into HIV Resistance -- |g 9.3.4. |t Binding of Maraviroc to CCR5 -- |g 9.4. |t Synthesis of Maraviroc -- |g 9.5. |t Nonclinical Safety and Toxicity Studies -- |g 9.5.1. |t Safety Pharmacology -- |g 9.5.2. |t Immuno- and Mechanistic Toxicity -- |g 9.6. |t Clinical Development of Maraviroc -- |g 9.6.1. |t Phase 1 Studies -- |g 9.6.2. |t Phase 2a Studies -- |g 9.6.3. |t Phase 2b/3 Studies -- |g 9.6.4. |t Development of Resistance to CCR5 Antagonists In Vivo -- |g 9.7. |t Summary, Future Directions, and Challenges -- |t Acknowledgments -- |t References -- |g ch. 10 |t Discovery Of Antimalarial Drug Artemisinin And Beyond / |r Ao Zhang -- |g 10.1. |t Introduction: Natural Products in Drug Discovery -- |g 10.2. |t Natural Product Drug Discovery in China -- |g 10.3. |t Discovery of Artemisinin: Background, Structural Elucidation and Pharmacological Evaluation -- |g 10.3.1. |t Background and Biological Rationale -- |g 10.3.2. |t Discovery of Artemisinin through Nontraditional Drug Discovery Process -- |g 10.3.3. |t Structural Determination of Artemisinin -- |g 10.3.4. |t Pharmacological Evaluation and Clinical Trial Summary of Artemisinin. |
| 880 | 0 | 0 | |6 505-01/(S |g Contents note continued: |g 10.4. |t Synthesis of Artemisinin -- |g 10.4.1. |t Synthesis of Artemisinin using Photooxidation of Cyclic or Acyclic Enol Ether as the Key Step -- |g 10.4.2. |t Synthesis of Artemisinin by Photooxidation of Dihydroarteannuic Acid -- |g 10.4.3. |t Synthesis of Artemisinin by Ozonolysis of a Vinylsilane Intermediate -- |g 10.5. |t SAR Studies of Structural Derivatives of Artemisinin: The Discovery of Artemether -- |g 10.5.1. |t C-10-Derived Artemisinin Analogs -- |g 10.5.2. |t C-9 and C-9,10 Double Substituted Analogs -- |g 10.5.3. |t C-3 Substituted Analogs -- |g 10.5.4. |t C-6 or C-7 Substituted Derivatives -- |g 10.5.5. |t C-11-Substituted Analogs -- |g 10.6. |t Development of Artemether -- |g 10.6.1. |t Profile and Synthesis of Artemether -- |g 10.6.2. |t Clinical Studies Aspects of Artemether -- |g 10.7. |t Conclusion and Perspective -- |t Acknowledgment -- |t References -- |g ch. 11 |t Discovery And Process Development Of MK-4965, A Potent Nonnucleoside Reverse Transcriptase Inhibitor / |r Jingjun Yin -- |g 11.1. |t Introduction -- |g 11.2. |t Discovery of MK-4965 -- |g 11.2.1. |t Background Information -- |g 11.2.2. |t SAR Studies Leading to the Discovery of MK-4965 -- |g 11.3. |t Preclinical and Clinical Studies of MK-4965 (19) -- |g 11.4. |t Summary of Back-Up SAR Studies of MK-4965 Series -- |g 11.5. |t Process Development of MK-4965 (19) -- |g 11.5.1. |t Medicinal Chemistry Route -- |g 11.5.2. |t Process Development -- |g 11.6. |t Conclusion -- |g 11.6.1. |t Lessons Learned from the Medicinal Chemistry Effort of MK-4965 Discovery -- |g 11.6.2. |t Summary and Lessons Learned from the Process Development of MK-4965 -- |t Acknowledgments -- |t References -- |g ch. 12 |t Discovery Of Boceprevir And Narlaprevir: The First And Second Generation Of HCV NS3 Protease Inhibitors / |r F. George Njoroge -- |g 12.1. |t Introduction -- |g 12.2. |t HCV NS3 Protease Inhibitors -- |g 12.3. |t Research Operation Plan and Biological Assays -- |g 12.3.1. |t Research Operation Plan -- |g 12.3.2. |t Enzyme Assay -- |g 12.3.3. |t Replicon Assay -- |g 12.3.4. |t Measure of Selectivity -- |g 12.4. |t Discovery of Boceprevir -- |g 12.4.1. |t Initial Lead Generation Through Structure-Based Drug Design -- |g 12.4.2. |t SAR Studies Focusing on Truncation, Depeptization, and Macrocyclisation -- |g 12.4.3. |t Individual Amino Acid Residue Modifications -- |g 12.4.4. |t Correlations Between P1, P3, and P3 Capping: The Identification of Boceprevir -- |g 12.5. |t Profile of Boceprevir -- |g 12.5.1. |t In Vitro Characterization of Boceprevir -- |g 12.5.2. |t Pharmacokinetics of Boceprevir -- |g 12.5.3. |t Interaction of Boceprevir with NS3 Protease -- |g 12.6. |t Clinical Development and Approval of Boceprevir -- |g 12.7. |t Synthesis of Boceprevir -- |g 12.8. |t Discovery of Narlaprevir -- |g 12.8.1. |t Criteria for the Back-up Program of Boceprevir -- |g 12.8.2. |t SAR Studies -- |g 12.8.3. |t Profile of Narlaprevir -- |g 12.8.4. |t Clinical Development Aspects of Narlaprevir -- |g 12.8.5. |t Synthesis of Narlaprevir -- |g 12.9. |t Summary -- |t References -- |g ch. 13 |t Discovery Of Samsca® (Tolvaptan): The First Oral Nonpeptide Vasopressin Receptor Antagonist / |r Yoshitaka Yamamura -- |g 13.1. |t Background Information about the Disease -- |g 13.2. |t Biological Rational -- |g 13.3. |t Lead Generation Strategies: The Discovery of Mozavaptan -- |g 13.4. |t Lead Optimization: From Mozavaptan to Tolvaptan -- |g 13.5. |t Pharmacological Profiles of Tolvaptan -- |g 13.5.1. |t Antagonistic Affinities of Tolvaptan for AVP Receptors -- |g 13.5.2. |t Aquaretic Effect Following a Single Dose in Conscious Rats -- |g 13.6. |t Drug Development -- |g 13.6.1. |t Synthetic Route of Discovery and Commercial Synthesis [10a] -- |g 13.6.2. |t Nonclinical Toxicology -- |g 13.6.3. |t Clinical Studies -- |g 13.7. |t Summary Focusing on Lessons Learned -- |t Acknowledgments -- |t References -- |g ch. 14 |t Silodosin (Urief®, Rapaflo®, Thrupas®, Urorec®, Silodix[™]): A Selective α1A Adrenoceptor Antagonist For The Treatment Of Benign Prostatic Hyperplasia / |r Junzo Kudoh -- |g 14.1. |t Background Information -- |g 14.1.1. |t Benign Prostatic Hyperplasia -- |g 14.1.2. |t α1-Adrenergic Receptors -- |g 14.2. |t Discovery of Silodosin -- |g 14.2.1. |t Medicinal Chemistry -- |g 14.2.2. |t Synthesis of Silodosin (Discovery Route) -- |g 14.2.3. |t Receptor Binding Studies -- |g 14.3. |t Pharmacology of Silodosin -- |g 14.3.1. |t Action Against Noradrenalin-Induced Contraction of Lower Urinary Tract Tissue -- |g 14.3.2. |t Actions Against Phenylephrine-Induced Increase in Intraurethral Pressure and Blood Pressure -- |g 14.3.3. |t Actions Against Intraurethral Pressure Increased by Stimulating Hypogastric Nerve and Blood Pressure in Dogs with Benign Prostatic Hyperplasia -- |g 14.3.4. |t Safety Pharmacology -- |g 14.4. |t Metabolism of Silodosin -- |g 14.5. |t Pharmacokinetics of Silodosin -- |g 14.5.1. |t Absorption -- |g 14.5.2. |t Organ Distribution -- |g 14.5.3. |t Excretion -- |g 14.6. |t Toxicology of Silodosin -- |g 14.7. |t Clinical Trials -- |g 14.7.1. |t Phase I Studies -- |g 14.7.2. |t Phase III Randomized, Placebo-Controlled, Double-Blind Study -- |g 14.7.3. |t Long-Term Administration Study -- |g 14.8. |t Summary: Key Lessons Learned -- |t References -- |g ch. 15 |t Raloxifene: A Selective Estrogen Receptor Modulator (Serm) / |r Henry U. Bryant -- |g 15.1. |t Introduction: SERMs -- |g 15.2. |t Benzothiophene Scaffold: A New Class of SERMs -- |g 15.3. |t Assays for Biological Evaluation of Tissue Selectivity -- |g 15.4. |t Benzothiophene Structure Activity -- |g 15.5. |t Synthesis of Raloxifene -- |g 15.6. |t SERM Mechanism -- |g 15.7. |t Raloxifene Pharmacology -- |g 15.7.1. |t Skeletal System -- |g 15.7.2. |t Reproductive System---Uterus -- |g 15.7.3. |t Reproductive System---Mammary -- |g 15.7.4. |t General Safety Profile and Other Pharmacological Considerations -- |g 15.8. |t Summary -- |t References. |
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