Phosphodiesterases: A Drug Target Family with Broad Therapeutic Impact

Published by: Drug and Market Development Publishing

Published: Aug. 1, 2005 - 188 Pages

Table of Contents

CHAPTER 1: EXECUTIVE SUMMARY

PDE Enzyme Families

Selective PDE Inhibitors

Technological Developments

Therapeutic Potential

Market Potential

Future Perspectives

CHAPTER 2: INTRODUCTION

Signal Transduction

Cyclic Nucleotides

cAMP

cGMP

Cyclic Nucleotide Phosphodiesterases

Objectives and Scope

CHAPTER 3: REVIEW OF PHOSPHODIESTERASE TARGET FAMILIES

History and Milestones

PDE Categorization and Nomenclature

PDE Families and Sub-Families

Nomenclature

General Molecular Biology

PDEs and Molecular Structure

Regulatory Domain

Catalytic Domain

C-terminal Domain

GAF Domain

PAS Domain

PDEs and Functional Characterization

PDEs and Tissue Distribution

PDEs and Physiological Processes

Review of PDE Families

PDE1

PDE1 and Molecular Biology

PDE1 and Therapeutic Potential

PDE2

PDE2 and Molecular Biology

PDE2 and Therapeutic Potential

PDE3

PDE3 and Molecular Biology

PDE3 and Therapeutic Potential

PDE4

PDE4 and Molecular Biology

PDE4 and Therapeutic Potential

PDE5

PDE5 and Molecular Biology

PDE5 and Therapeutic Potential

PDE6

PDE6 Molecular Biology

PDE6 and Therapeutic Potential

PDE7

PDE7 and Molecular Biology

PDE7 and Therapeutic Potential

PDE8

PDE8 and Molecular Biology

PDE8 and Therapeutic Potential

PDE9

PDE9 and Molecular Biology

PDE9 and Therapeutic Potential

PDE10

PDE10 and Molecular Biology

PDE10 and Therapeutic Potential

PDE11

PDE11 and Molecular Biology

PDE11 and Therapeutic Potential

CHAPTER 4: SELECTIVE PHOSPHODIESTERASE INHIBITORS AND CURRENT DRUG PIPELINES

Introduction

PDEs as Attractive Drug Targets

Selective PDE5 Inhibitors

Approved PDE5 Inhibitors

Viagra®

Levitra®

Cialis®

Pipeline PDE5 Inhibitors

Selective PDE3 Inhibitors

Approved PDE3 Inhibitors

Pletal®

Pipeline PDE3 Inhibitors

Selective PDE4 Inhibitors

Phase III PDE4 Inhibitors

Daxas®

Ariflo®

Phase II PDE4 Inhibitors

Phase I PDE4 Inhibitors

Preclinical PDE4 Inhibitors

Selective PDE Inhibitors and Other PDE Families

CHAPTER 5: TECHNOLOGY AND APPROACHES TO PDE DRUG DISCOVERY

Introduction

Functional Studies of PDEs as Drug Targets

PDEs and Target Biology

PDEs, Protein Purification and Pharmacological Profiling

Knockout Technology

RNA Technologies

Population Genetics Approach

Structural Studies of PDEs as Drug Targets

Crystallography

PDEs and Crystallography

PDE Crystallography in Industry

PDEs and Co-crystallization

Structure-based Drug Design

Scaffold-based Drug Discovery

Structural Chemoproteomics

PDEs and Diagnostics

CHAPTER 6: CURRENT CHALLENGES IN PDE INHIBITOR DEVELOPMENT

Introduction

Desired Inhibitor Characteristics and Associated Challenges

Safety

Efficacy

Selectivity

Potency

Chronology of PDE Inhibitor Development

Nonselective PDE Inhibitors

Selective PDE Inhibitors

First Generation PDE Inhibitors

Second Generation PDE Inhibitors

Third Generation PDE Inhibitors

Summary of Current Challenges

CHAPTER 7: THERAPEUTIC POTENTIAL AND SELECTIVE PDE INHIBITORS

Introduction

Erectile Dysfunction

Peripheral Arterial Disease

Asthma

COPD

Learning and Memory Disorders

Depression

Cross-indications

Other Diseases

CHAPTER 8: MARKET POTENTIAL AND SELECTIVE PDE INHIBITORS

Introduction

Market Activity Per PDE Inhibitor Family

Selective PDE5 Inhibitors

Viagra®

Levitra®

Cialis®

Selective PDE3 Inhibitors

Pletal®

Market Activity per Therapeutic Area

The Erectile Dysfunction Market

The Peripheral Arterial Disease Market

The Asthma Market

The COPD Market

The CNS Market

Market Landscape

Market Potential

Future of Approved PDE Inhibitors

Future of Pipeline PDE Inhibitors

PDE5 Inhibitors

PDE4 Inhibitors

PDE Inhibitors and Other PDE Families

CHAPTER 9: FUTURE PERSPECTIVES

Introduction

PDEs and Therapeutic and Market Potential

Realizing the Therapeutic Potential

Realizing the Market Potential

PDE Inhibitor Discovery

PDE Isoform Characterization

Technology Developments

PDE’s and Clinical Pipeline

PDEs and the Patient

Summary

CHAPTER 10: COMPANY PROFILES

ALTANA Pharma AG

Bayer HealthCare

Celgene Corporation

CrystalGenomics, Inc.

deCODE genetics

elbion AG

GlaxoSmithKline plc

Glenmark Pharmaceuticals Ltd

ICOS Corporation

Inflazyme Pharmaceuticals Ltd

Memory Pharmaceuticals Corporation

Nissan Chemical Industries Ltd

Otsuka America Pharmaceutical, Inc.

Pfizer, Inc.

Plexxikon, Inc.

Schering Plough Corporation

SEQUENOM, Inc.

Wyeth

VIVUS, Inc.

CHAPTER 11: INTERVIEW WITH INDUSTRY EXPERTS

John Dietrich, PhD., VIVUS, Inc.

Gideon Bollag, Ph.D., Plexxikon, Inc. (Berkeley, California)

Thomas Kronbach Ph.D., elbion AG (Radebeul, Germany)

Cesare Mondadori, Ph.D., Neuro3d S.A (Mulhouse, France)

Dr. Swaroop Kumar Vakkalanka, Glenmark Pharmaceuticals Ltd.

CHAPTER 12: REFERENCES

TABLE OF EXHIBITS

Exhibit 2.1 cAMP Synthesis from ATP

Exhibit 2.2 cAMP Degradation and PDEs

Exhibit 2.3 cGMP synthesis from GTP

Exhibit 2.4 cGMP Degradation and PDEs

Exhibit 3.1 History and Milestones Associated with PDEs

Exhibit 3.2 PDE Families, Sub-families/Genes and Cyclic Nucleotide Substrate(s)

Exhibit 3.3 Common Domain Distribution

Exhibit 3.4 Unique Domain Organization per PDE Family

Exhibit 3.5 PDE Families with GAF Domains

Exhibit 3.6 Examples of Tissue Distribution of Human PDEs

Exhibit 3.7 Select Physiological Processes Associated with PDEs

Exhibit 3.8 PDE1 Genes and Splice Variants

Exhibit 3.9 PDE2 Gene and Splice Variants

Exhibit 3.10 PDE3 Genes and Splice Variants

Exhibit 3.11 PDE4 Genes and Splice Variants

Exhibit 3.12 PDE5 Gene and Splice Variants

Exhibit 3.13 PDE6 Genes and Splice Variants

Exhibit 3.14 PDE7 Genes and Splice Variants

Exhibit 3.15 PDE8 Genes and Splice Variants

Exhibit 3.16 PDE9 Gene and Splice Variants

Exhibit 3.17 PDE10 Gene and Splice Variants

Exhibit 3.18 PDE11 Gene and Splice Variant

Exhibit 4.1 Approved PDE5 Inhibitors

Exhibit 4.2 Pipeline PDE5 Inhibitors

Exhibit 4.3 Approved and Pipeline PDE3 Inhibitors

Exhibit 4.4 Pipeline PDE4 Inhibitors

Exhibit 5.1 Schematic Diagram of RNA Interference

Exhibit 5.2 Resolution of PDE Crystal Structures

Exhibit 5.3 The Pipeline at CrystalGenomics, Inc

Exhibit 6.1 Selectivity of PDE4 Inhibitors

Exhibit 6.2 IC50 (nmol/L) of Approved PDE5 Inhibitors

Exhibit 6.3 Pipeline of PDE4 Inhibitors Withdrawn from Development

Exhibit 7.1 Therapeutic Areas and Active Companies in PDE Drug Discovery

Exhibit 7.2 Cellular Mechanism of Action of PDE5 Inhibitors

Exhibit 7.3 Key Physiological and Cellular Characteristics of Asthma

Exhibit 7.4 Potential Anti-inflammatory and Immunomodulatory Effects of PDE4 Inhibitors

Exhibit 7.5 Effects of cAMP Relevant to COPD

Exhibit 8.1 2004 Sales of Approved Selective PDE Inhibitors

Exhibit 8.2 Sales Revenue from the PDE5 Inhibitor Viagra® (1999-2004)

Exhibit 8.3 Press Release Titles from Pfizer Relating to Viagra®

Exhibit 8.4 Press Release Titles from Bayer AG Relating to Levitra®

Exhibit 8.5 Press Release Titles and Achievements of ICOS Corp. Relating to Cialis®

Exhibit 8.6 Categorization of Companies Active in PDE Drug Discovery

Abstract

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