Liras / Bell Phosphodiesterases and Their Inhibitors

1. Auflage 2014
ISBN: 978-3-527-68235-5
Verlag: Wiley-VCH
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band 61, 240 Seiten, E-Book

Reihe: Methods and Principles in Medicinal Chemistry

Written by the pioneers of Viagra, the first blockbuster PDE inhibitor drug. Beginning with a review of the first wave of phosphodiesterase (PDE) inhibitors, this book focuses on new and emerging PDE targets and their inhibitors. Drug development options for all major human PDE families are discussed and cover diverse therapeutic fields, such as neurological/psychiatric, cardiovascular/metabolic, pain, and allergy/respiratory diseases. Finally, emerging chemotherapeutic applications of PDE inhibitors against malaria and other tropical diseases are discussed.

Autoren/Hrsg.

Liras, Spiros

Bell, Andrew S.

Weitere Mitwirkende

Mannhold, Raimund

Kubinyi, Hugo

Folkers, Gerd

Inhaltsverzeichnis

INTRODUCTION   TOWARD A NEW GENERATION OF PDE5 INHIBITORS THROUGH ADVANCES IN MEDICINAL CHEMISTRY Introduction The First-Generation Agents PDE5 as a Mechanism and Alternative Indications Beyond MED A Summary of PDE5 Chemotypes Reported Post-2010 Second-Generation PDE5 Inhibitors from Pfizer: Pyrazolopyrimidines Second-Generation PDE5 Inhibitors from Pfizer: Pyridopyrazinones Conclusions   PDE4: NEW STRUCTURAL INSIGHTS INTO A REGULATORY MECHANISM AND IMPLICATIONS FOR THE DESIGN OF SELECTIVE INHIBITORS Introduction Isoforms, Domain Organizations, and Splice Variants Structural Features of the Catalytic Site Regulation of PDE4 Activity Crystal Structure of Regulatory Domains of PDE4 URC2 Interaction and Selectivity Conclusions   PDE4: RECENT MEDICINAL CHEMISTRY STRATEGIES TO MITIGATE ADVERSE EFFECTS Introduction Brief Summary of pan-PDE4 Inhibitors PDE4 Strategies to Avoid Gastrointestinal Events Conclusions   THE FUNCTION, ENZYME KINETICS, STRUCTURAL BIOLOGY, AND MEDICINAL CHEMISTRY OF PDE10A Enzymology and Protein Structure Papaverine-Related PDE10A Inhibitors MP-10/PF-2545920 Class of Inhibitors PF-2545920/MP-Inspired Inhibitors PF-2545920/Papaverine/Quinazoline Hybrid Series of Inhibitors PET Ligand Development Summary and Future   THE STATE OF THE ART IN SELECTIVE PDE2A INHIBITOR DESIGN Introduction Selective PDE2A Inhibitors Methods Conclusions   CRYSTAL STRUCTURES OF PHOSPHODIESTERASE 9A AND INSIGHT INTO INHIBITOR DISCOVERY Introduction Subtle Asymmetry of the PDE9 Dimer in the Crystals The Structure of the PDE9 Catalytic Domain Interaction of Inhibitors with PDE9 Implication on Inhibitor Selectivity   PDEs AS CNS TARGETS: PDE9 INHIBITORS FOR COGNITIVE DEFICIT DISEASES PDE9A Enzymology and Pharmacology Crystal Structures of PDE9A Inhibitors Medicinal Chemistry Efforts toward Identifying PDE9A Inhibitors for Treating Cognitive Disorders Analysis of CNS Desireability of PDE9A Inhibitors Conclusions   PHOSPHODIESTERASE 8B Introduction Identification Properties Expression and Tissue Distribution Functions of PDE8B Inhibitors and Potential Therapeutic Uses   SELECTIVE NEW SMALL-MOLECULE INHIBITORS OF PHOSPHODIESTERASE 1 Introduction PDE1 Enzymology PDe1 Inhibitors Conclusion   RECENT ADVANCES IN THE DEVELOPMENT OF PDE7 INHIBITORS Introduction Historical Development of PDE7 Inhibitors Recent Advances in the Discovery of PDE7 Inhibitors for Peripheral Therapeutic Benefit Recent Advances in the Discovery of PDE7 Inhibitors for CNS-Related Disorders Recent Advances in the Discovery of Dual PDE7 Inhibitors Identifying Next-Generation PDE7 Inhibitors Summary   INHIBITORS OF PROTOZOAN PHOSPHODIESTERASES AS POTENTIAL THERAPEUTIC APPROACHES FOR TROPICAL DISEASES Introduction Malaria Chagas Disease Leishmaniasis Human African Trypanosomiasis Conclusion   Index

Über Autor(innen)

Spiros Liras is the head of the cardiovascular metabolic and endocrine diseases (CVMED) medicinal chemistry department at Pfizer R&D in Cambridge, MA (USA). Previously, he was Senior Director of medicinal chemistry in Neuroscience at Pfizer, working on treatments for addiction, depression, schizophrenia, cognition and Alzheimer's disease. In Neuroscience he worked on multiple PDE targets for the treatment of neuropsychiatric diseases including PDE10, PDE9, PDE2 and PDE1. Dr. Liras obtained his PhD in organic chemistry in 1989 from Iowa State University. He joined Pfizer in 1994 after postdoctoral studies at the University of Texas at Austin. He is a coauthor in more than 70 publications and patents.   Andrew Bell was with Pfizer for over 30 years, following studies at York University (UK). He spent his early career working on PDE inhibitors leading to the inotrope/ vasodilator (PDE3) candidate, nanterinone, and the PDE5 inhibitor, sildenafil (Viagra, Revatio). Soon after the launch of sildenafil in 1998, he was given responsibility for File Enrichment, as part of Pfizer's collaborations with ArQule and Tripos. He has subsequently applied the results of the File Enrichment investment to generate new lead series for multiple projects, including novel series of selective PDE- 4,5,8 and 9 inhibitors. He is currently involved in research into parasitic diseases at Imperial College, London.