Lead Optimization A Reinvention of the Process

Table of Contents

Section Summary

1 Executive Summary

2 Introduction

• Lead Optimization as an Integral Part of Drug Discovery

3 Background and Strategy

• What is an "Optimized Lead Molecule?"
• Why Preclinical Candidates are Discontinued: Starting Points for Lead Optimization
• Economy: The Impact of Compound Attrition at Various Stages
• Tuning Lead Discovery towards Later Lead Optimization
• Outsourcing Medicinal Chemistry: Lead Optimization By Third Parties

4 The Technology of Lead Optimization - In Vitro and In Silico

• Technology of Lead Optimization - A Paradigm Change
• The Parallel Synthesis Approach
• Measuring, Modifying and Predicting Physico-Chemical Properties
• Molecular Modeling and Docking: Modifying a Pharmacophore In Silico
• Experimental Determination of Interaction Mode and QSARs in Solution
• Predictive ADMET: The Greatest Challenge
• Pharma Informatics: Bringing It All Together

5 Patenting and Regulatory Affairs: More Than Just Paperwork

• Lead Optimization and Intellectual Property
• Regulatory Issues In Lead Optimization

6 Case Studies In Lead Optimization

• Anti-Tumor and Neuroprotective Kinase Inhibitors Derived From K-252
• Second-Generation Galantamine Congeners
• HIV Protease Inhibitors
• The Bisphosphonates - A Story of Evolution in Osteoporosis Drugs

7 Profiles of Selected Companies In The Lead Optimization Business

8 Summary and Outlook

9 Companies Mentioned In This Report