Phosphodiesterases and Their Inhibitors

by Liras, Spiros; Bell, Andrew S.; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

• ISBN13: 9783527332199
• ISBN10: 3527332197
• Edition: 1st
• Format: Hardcover
• Copyright: 2014-06-09
• Publisher: Wiley-VCH

Summary

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.

Author Biography

Spiros Liras is the head of the cardiovascular metabolic and endocrine diseases (CVMED) medicinal chemistry department at Pfizer R&D in Groton (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. Dr. Liras obtained a Ph.D. in organic chemistry in 1989 from Iowa State University. Subsequently, he joined the group of Professor Stephen F. Martin at the University of Texas at Austin as a postdoctoral fellow. He is the author or coauthor of more than 50 publications and patents.

Andrew Bell has been with Pfizer for over 30 years, following studies at York University (UK). He spent the first 9 years of his career working on PDE inhibitors leading to the inotrope/vasodilator (PDE3) candidate, nanterinone, and the PDE5 inhibitor, sildenafil (Viagra, Revatio). Soon after the discovery of sildenafil in 1989, he moved to antifungals research until 1999, when he was given responsibility for File Enrichment, as part of Pfizer's collaborations with ArQule and Tripos. He has subsequently been working in the hit-to-lead arena in Pfizer's Sandwich and Groton Laboratories, making use of the File Enrichment investment to generate new lead series for multiple projects, including novel series of selective PDE inhibitors. Dr. Bell was awarded one of the 2008 Awards for Technical Achievements in Organic Chemistry by the American Chemical Society.

Table of Contents

INTRODUCTION
The PDE gene family in drug discovery
The origins of drugability: The discovery of PDE-5 inhibitors for erectile dysfunction
Recent advances and new therapeutic utilities for PDE-5 inhibitors

PSYCHIATRIC AND NEUROLOGICAL DISORDERS
General overview
PDE-10 inhibitors for schizophrenia
PDE-9 inhibitors for cognitive deficits diseases
PDE-4 inhibitors for CNS indications
PDE-2 inhibitors for CNS indications

CARDIOVASCULAR AND METABOLIC DISEASES
General overview
PDE-8 inhibitors for the treatment of diabetes
PDE-7/8 inhibitors

PAIN THERAPY
PDE-7 inhibitors for the treatment of pain

ALLERGY AND RESPIRATORY DISEASES
PDE-4 inhibitors as treatments for allergy and respiratory disease
Selective PDE inhibitors for COPD

NON-MAMMALIAN TARGETS
Malaria PDEs
Trypanosome cruzei PDEs

STRUCTRUAL BIOLOGY OF PHOSPHODIESTERASES
Impact of PDE structural biology on drug discovery
Structural biology of PDE-1 and PDE-4 inhibitors