INTRODUCTION TO DRUG METABOLISM
CONTENTS PART I: CENTRAL NERVOUS SYSTEM DISEASES – ROBICHAUD CHAPTER POTENTIAL CNS APPLICATIONS FOR PHOSPHODIESTERASE ENZYME INHIBITORS 1 INTRODUCTION 2 PDE2 INHIBITORS 3 PDE4 INHIBITORS 4 PDE9 INHIBITORS 5 PDE10 INHIBITORS 6 PDE11 INHIBITORS 7 SUMMARY REFERENCES CHAPTER RECENT DEVELOPMENTS IN MONOAMINE REUPTAKE INHIBITORS 2 SINGLE ACTION REUPTAKE INHIBITORS 3 DUAL REUPTAKE INHIBITORS 4 TRIPLE REUPTAKE INHIBITORS (TRIS) 5 CONCLUSION SECRETASE INHIBITORS AND MODULATORS FOR THE TREATMENT OF ALZHEIMER’S DISEASE 2 INHIBITORS OF BACE 3 INHIBITORS OF G-SECRETASE 4 MODULATORS OF G-SECRETASE 5 SUMMARY RECENT ADVANCES IN DRUG DISCOVERY OF HISTAMINE H3 ANTAGONISTS 2 CLINICAL APPLICATIONS OF H3 RECEPTOR ANTAGONISTS 3 PHARMACOPHORES AND MODELING 4 DESIGN STRATEGIES AND STRUCTURE–ACTIVITY ADVANCES 5 H3 ANTAGONISTS WITH A DUAL MECHANISM 6 FUTURE PERSPECTIVES RECENT ADVANCES IN THE TREATMENT OF INSOMNIA ´ 1 INTRODUCTION 2 GABAA RECEPTOR MODULATORS 3 MELATONIN RECEPTOR AGONISTS 4 OREXIN RECEPTOR ANTAGONISTS 5 HISTAMINERGIC AND SEROTONINERGIC MODULATORS 6 CONCLUDING REMARKS ADVANCES IN TRANSIENT RECEPTOR POTENTIAL MODULATORS 2 SMALL MOLECULE TRP MODULATORS 3 CONCLUSION PART II: CARDIOVASCULAR AND METABOLIC DISEASES – STAMFORD CHAPTER CASE HISTORY: JANUVIATM (SITAGLIPTIN), A SELECTIVE DIPEPTIDYL PEPTIDASE IV INHIBITOR FOR THE TREATMENT OF TYPE 2 DIABETES 2 PATHOGENESIS OF TYPE 2 DIABETES 3 RATIONALE FOR THE USE OF DPP-4 INHIBITORS TO TREAT TYPE DIABETES 4 MRL’S DPP-4 INHIBITOR PROGRAM: THREO- AND ALLO-ISOLEUCYL THIAZOLIDIDES 5 MEDICINAL CHEMISTRY EFFORTS LEADING TO SITAGLIPTIN 6 PROPERTIES OF ANALOG 27 AND SITAGLIPTIN 7 CLINICAL STUDIES OF SITAGLIPTIN 8 CONCLUSION CATHEPSIN K INHIBITORS 2 NEW BIOLOGY 3 RECENT ADVANCES IN INHIBITOR DESIGN 4 CLINICAL DATA 5 CONCLUSIONS ACKNOWLEDGEMENT NEW NONPEPTIDE-BINDING GPCRS AS TARGETS FOR DIABETES AND THE METABOLIC SYNDROME 3 GPR40 FAMILY 6 GPR109A AND GPR109B 7 CONCLUSIONS CHAPTER 10 NOVEL SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) 2 SERMS FOR HOT FLUSHES 3 OVARIAN SELECTIVE SERMS 4 ERA SELECTIVE SERMS 5 OTHER NOVEL SERM SCAFFOLDS 6 STEROID-DERIVED SCAFFOLDS 7 NONCLASSICAL ESTROGEN SIGNALING LIPID-METABOLIZING ENZYMES AS TARGETS FOR DYSLIPIDEMIA AND INSULIN RESISTANCE 2 LIPID ABSORPTION AND MOBILIZATION 3 TRIGLYCERIDE SYNTHESIS 4 FATTY ACID SYNTHESIS AND METABOLISM RECENT TRENDS IN HDL MODULATING THERAPIES 2 HDL AND ATHEROSCLEROSIS 3 SCOPE AND LIMITATIONS OF MARKETED THERAPIES 4 EMERGING CLINICAL COMPOUNDS 5 PRE-CLINICAL DEVELOPMENTS 6 CONCLUSION PART III: IN?AMMATION/PULMONARY/GI – BARRISH CHAPTER CASE HISTORY ON TEGASEROD (ZELNORMS/ZELMACS) 2 DISCOVERY OF THE 5-HT4 RECEPTOR IN THE GI TRACT 3 TEST SYSTEMS ADDRESSING 5-HT4 RECEPTOR AGONIST ACTIVITY 4 FROM SEROTONIN TO TEGASEROD 5 PRO?LING STUDIES 6 CLINICAL PHASE II/III STUDIES 7 CONCLUSION ADVANCES IN THE DISCOVERY OF CC CHEMOKINE RECEPTOR ANTAGONISTS 2 RECENT BIOLOGY 3 RECENT MEDICINAL CHEMISTRY 4 CONCLUSION SEMICARBAZIDE SENSITIVE AMINE OXIDASE AND VASCULAR ADHESION PROTEIN-1: ONE PROTEIN BEING VALIDATED AS A THERAPEUTIC TARGET FOR IN?AMMATORY DISEASES 2 MOLECULAR BIOLOGY OF THE COPPER-CONTAINING AMINE OXIDASE FAMILY 3 CO-FACTOR AND MECHANISM OF THE AMINE OXIDASE ACTIVITY 4 STRUCTURAL BIOLOGY 5 THERAPEUTIC OPPORTUNITIES 6 DRUG DISCOVERY 7 SSAO/VAP-1 INHIBITORS 9 ABBREVIATIONS SPHINGOSINE 1-PHOSPHATE TYPE 1 RECEPTOR MODULATORS: RECENT ADVANCES AND THERAPEUTIC POTENTIAL 2 S1P1 AGONISTS 3 S1P1 ANTAGONISTS 4 CONCLUSIONS MAP KINASE INHIBITORS IN IN?AMMATION AND AUTOIMMUNE DISORDERS 2 INHIBITORS OF ERK PATHWAY 3 INHIBITORS OF JNK PATHWAY 4 INHIBITORS OF P38 PATHWAY PART IV: CANCER AND INFECTIOUS DISEASES – MYLES CHAPTER RECENT PROGRESS ON NOVEL HCV INHIBITORS 2 NOVEL COMPOUNDS IN THE DISCOVERY/PRECLINICAL STAGE SMALL MOLECULE CCR5 AND CXCR4-BASED VIRAL ENTRY INHIBITORS FOR ANTI-HIV THERAPY CURRENTLY IN DEVELOPMENT 2 CCR5 INHIBITORS 3 CXCR4 INHIBITORS NOTE SMALL-MOLECULE INHIBITORS OF GLUTATHIONE S-TRANSFERASE P1-1 AS ANTICANCER THERAPEUTIC AGENTS 2 TYPES OF INHIBITORS 3 CONCLUSIONS RECENT ADVANCES IN THE MEDICINAL CHEMISTRY OF HISTONE DEACETYLASE INHIBITORS 2 ZINC-DEPENDENT HDAC INHIBITORS 3 NAD-DEPENDENT HDAC MODULATORS NEW DEVELOPMENTS IN ANTIBACTERIAL DRUG R&D 2 UPDATES OF ESTABLISHED CLASSES OF ANTIBIOTICS 3 FUTURE ANTIBACTERIAL PIPELINE: INHIBITORS OF NEW TARGETS 4 FUTURE OUTLOOK SMALL MOLECULE INHIBITORS OF AKT/PKB KINASE AS A STRATEGY FOR TREATING CANCER 2 PI3K/AKT KINASE PATHWAY INHIBITORS IN PRE-CLINICAL DEVELOPMENT 3 PI3K/AKT KINASE PATHWAY INHIBITORS IN CLINICAL TRIALS PART V: TOPICS IN BIOLOGY – LOWE CHAPTER SPLEEN TYROSINE KINASE (SYK) BIOLOGY, INHIBITORS AND THERAPEUTIC APPLICATIONS 2 SYK KINASE 3 STRUCTURAL BIOLOGY OF SYK KINASE 4 SYK KINASE AS A THERAPEUTIC TARGET FOR DISEASE 5 STATUS OF SMALL MOLECULE INHIBITORS OF SYK KINASE SYSTEMS BIOLOGY AND KINASE SIGNALING 1 COMPLEXITY AND SCOPE IN SYSTEMS KINASE BIOLOGY 2 POSITIVE AND NEGATIVE FEEDBACK LOOPS 3 AN EXAMPLE OF THE PRACTICAL APPLICATION OF SYSTEMS BIOLOGY: ERBB SIGNALING 5 ACRONYMS USED THE MOLECULAR LIBRARIES SCREENING CENTER NETWORK (MLSCN): IDENTIFYING CHEMICAL PROBES OF BIOLOGICAL SYSTEMS 2 ROLE OF CHEMISTRY IN THE MLSCN 3 NOVEL PROBES FROM THE MLSCN 4 FUTURE OUTLOOK AND CONCLUSIONS THE APPLICATION OF TRANSCRIPTIONAL PRO?LING IN MODEL CONNECTIVITY AND LEAD ASSESSMENT IN DRUG DISCOVERY 2 TRANSCRIPTIONAL PRO?LING TECHNOLOGY: STATE OF THE ART, AND FORESEEABLE FUTURE 3 INTERCONNECTING DISEASE, TARGET VALIDATION MODELS, AND PHARMACOLOGICAL RESPONSE 4 COMPARING SELECTIVITY OF PHARMACOLOGICAL RESPONSE IN LEAD ASSESSMENT PART VI: TOPICS IN DRUG DESIGN AND DISCOVERY – DESAI CHAPTER FRAGMENT-BASED LEAD DISCOVERY 2 EXAMPLES OF FRAGMENT HIT IDENTI?CATION 3 EXAMPLES OF FRAGMENTS PROGRESSED INTO NANOMOLAR LEADS 4 COMMENTARY AND DISCUSSION OF KEY CONCEPTS 5 OUTLOOK COMPUTATIONAL MODELS FOR ADME 2 BASIC COMPUTED DESCRIPTORS FOR DRUG-LIKENESS 3 SOLUBILITY 4 INTESTINAL ABSORPTION 5 BLOOD–BRAIN-BARRIER PENETRATION 6 METABOLISM PREDICTION OF HUMAN VOLUME OF DISTRIBUTION USING IN VIVO, IN VITRO, AND IN SILICO APPROACHES 2 DEFINITIONS OF VOLUME OF DISTRIBUTION 3 PREDICTING HUMAN VOLUME OF DISTRIBUTION FROM CHEMICAL, IN VITRO, AND IN VIVO DATA PLASMA PROTEIN BINDING AND THE FREE DRUG PRINCIPLE: RECENT DEVELOPMENTS AND APPLICATIONS 2 RE?NEMENTS IN UNDERSTANDING OF THE FREE DRUG PRINCIPLE 3 APPLICATIONS FROM THE MEDICINAL CHEMISTRY LITERATURE 4 COMPUTATIONAL STUDIES 5 EXCEPTIONS TO THE FREE DRUG PRINCIPLE 6 ADVANCES IN METHODOLOGY FOR MEASURING PLASMA PROTEIN BINDING PART VII: TO MARKET, TO MARKET – TO MARKET, TO MARKET –