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Phosphodiesterases and Their Inhibitors

  • Erscheinungsdatum: 03.03.2014
  • Verlag: Wiley-VCH
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Phosphodiesterases and Their Inhibitors

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. 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.

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Phosphodiesterases and Their Inhibitors

1
Introduction

Andrew S. Bell and Spiros Liras

The cyclic nucleotide phosphodiesterases (PDEs) are a group of regulatory enzymes that affect intracellular signaling by inactivating the second messengers cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) to the corresponding nucleotides ( Figure 1.1 ). The PDEs are critical in maintaining levels of these cyclic nucleotides within the narrow tolerances required for normal cell operation.

Figure 1.1 Hydrolysis of cyclic nucleotides by PDEs.

The superfamily of PDEs is encoded by 21 different genes that are grouped into 11 subfamilies according to primary sequence homology, composition of the N-terminal regulatory domain, and inhibitor sensitivity. The family has also been split into three sets based on their substrate preferences ( Table 1.1 ). In addition, more than 60 splice variants have been reported.

Table 1.1 Substrate preferences of each class of PDE
cAMP-specific cGMP-specific Mixed
PDE4

PDE5

PDE1

PDE7

PDE6

PDE2

PDE8

PDE9

PDE3

PDE10

PDE11

Signal transduction cascades regulated by the PDEs are diverse and include a multitude of central and peripheral processes, such as cell proliferation and cell death, neuroplasticity, gene activation, insulin reaction, locomotion, neurotransmission, metabolism, vascular smooth muscle contraction and growth, and olfactory, taste, and visual responses. Pharmacological intervention of these signaling cascades through selective PDE inhibition is of great therapeutic interest for both central and peripheral targets.

The biological importance and druggability of these enzymes have led to market success with inhibitors for three of the PDE family members across multiple diseases ( Table 1.2 ). The earliest examples include the PDE3 inhibitors amrinone and milrinone for cardiovascular indications, followed by PDE4 inhibitor roflumilast for severe chronic obstructive pulmonary disease. Unfortunately, both PDE3 and PDE4 inhibition result in highly undesirable side effects: sudden cardiac arrest and severe nausea, respectively. As a result, research into novel PDE inhibitors diminished in the late 1980s.

Table 1.2 Peak sales of PDE inhibitors, post-1997
USAN Structure Launch date Target Indication Peak sales ($, million) Amrinone 1983 PDE3 Cardiotonic 20 Milrinone 1989 PDE3 Cardiotonic 228 Roflumilast 2010 PDE4 COPD 104 Sildenafil 1998 PDE5 MED/PH 3119 Vardenafil 2003 PDE5 MED 517 Tadalafil 2003 PDE5 MED/PH/BPH 2222 Udenafil 2009 PDE5 MED 24 Mirodenafil 2009? PDE5 MED 7.5 Avanafil 2012 PDE5 MED 2.4 /

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