Progress in Medicinal Chemistry

Preface v List of Contributors ix Hit and Lead Identification: Efficient Practices for Drug Discovery 1(62) Robert A. Goodnow, Jr. Paul Gillespie Introduction 1(1) Hit and Lead Identification Practices 2(9) Sources of Initial Hits and Leads 2(5) The Hit-to-Lead Process: General Themes and Considerations 7(4) Lead Identification as Reported for Specific Targets 11(38) Melanin-Concentrating Hormone-1 Receptor Antagonist 11(16) Dipeptidyl Peptidase IV Inhibitors 27(9) CDK1/CDK2 Inhibitors 36(13) Conclusion 49(1) References 50(13) DPPIV Inhibition: Promising Therapy for the Treatment of Type 2 Diabetes 63(48) Paul E. Wiedeman Introduction 64(7) Type 2 Diabetes Pandemic 64(1) Inhibition of DPPIV as a Strategy to Enhance the Incretin Effect 64(2) Dipeptidyl Peptidase IV 66(2) Potential for Disease Modification with DPPIV Inhibitors 68(1) Importance of DPPIV Selectivity 68(1) Structural Biology 69(2) Medicinal Chemistry and Preclinical Studies 71(25) Early DPPIV Inhibitors 71(3) Covalent DPPIV Inhibitors: P2 Secondary Amine Analogues 74(6) Covalent DPPIV Inhibitors: P2 Primary Amine Analogues 80(4) Non-Covalent DPPIV Inhibitors: P2 Primary Amine Analogues 84(5) Peptide DPPIV Inhibitors that Extend into P1' 89(1) Non-Peptidic/Non-Covalent DPPIV Inhibitors 90(6) Clinical Data for Oral DPPIV Inhibitors 96(5) Conclusions 101(1) Authors Note 102(1) References 102(9) Recent Progress Toward Nonpeptide Ligands for the Melanocortin-4 Receptor 111(58) Chen Chen Introduction 112(3) Melanocortin Receptors 112(3) Cyclohexylpiperidines as Potent MC4R Agonists 115(11) Tetrahydroisoquinoline (THIQ) and Analogues 115(6) MB243 and Related Compounds 121(4) Other THIQ-Related Compounds 125(1) Cyclohexylpiperazines and Phenylpiperidines 126(2) Phenylpiperazines as MC4R Agonists 128(5) Other Classes of MC4R Agonists 133(2) Compounds Mimicking α-MSH and Its Peptide Analogues 135(2) From Agonists to Antagonists 137(4) Small Molecule MC4R Antagonists from Initial Screen Hits 141(3) Other Nonpeptide MC4R Ligands 144(1) Interaction of the MC4R with Ligands 145(10) Structural Information of Melanocortin Peptides 145(1) Small Peptide Ligands with HFRW Variants 146(2) Conformations of Peptide Ligands 148(1) Receptor Structure Information through Mutagenesis Studies 149(3) Computational Modeling of the Human MC4R 152(1) Possible Interaction of Nonpeptide Ligands with the MC4-Receptor 153(2) Medicinal Chemistry 155(3) Conclusion 158(1) References 159(10) Tuberculosis Chemotherapy: Recent Developments and Future Perspectives 169(40) Veemal Bhowruth Lynn G. Dover Gurdyal S. Besra Introduction 170(3) Drug Resistance and Development of Modern Anti-TB Chemotherapy 171(2) TB Drug Development Pipeline 173(14) Diarylquinolone TMC207 173(1) n-Octanesulfonylacetamide (OSA) 174(2) Phenothiazines 176(1) Oxazolidinones 176(2) Quinolones 178(1) Azoles 179(1) Nitroimidazopyran PA-824 180(1) Dihydroimidazo-oxazole OPC 67683 181(1) Sudoterb (Pyrrole LL-4858) 181(1) Peptide Deformylase Inhibitor BB-3497 182(1) Acetohydroxyacid Synthase Inhibitor KHG20612 182(1) Ethambutol Analogue SQ109 183(1) Thiolactomycin 183(1) Siderophore Biosynthesis 184(2) Purine Analogues 186(1) Potential New Drug Targets 187(7) Targeting Mycobacterial Persistence 187(3) The Stringent Response 190(2) Unexplored Targets in Cell Wall Biosynthesis 192(2) Concluding Comments 194(1) Acknowledgments 195(1) References 196(9) Subject Index 205(4) Author Index (Vols. 1--45) 209(6) Subject Index (Vols. 1--45) 215