リード化合物の最適化：創薬プロセスの改革

The ability to generate a sufficient number of candidate compounds that can be taken into the formal stages of drug development has always been essential to the pharmaceutical industry. The industry's present productivity crisis can be traced to two causes: development processes take too long, and their attrition profile is far from optimal - with too many candidates failing during the later stages when considerable resources have already been spent on them. Lead optimization is the procedural hub that determines the chances for eventual success of a drug. Companies have already realized that improving R&D productivity is contingent on the full integration of lead optimization into discovery and development. Although this will not lead to the disappearance of lead optimization as a discrete step in the process, from the beginning all its requirements need to be considered.

D&MD's Technology Forecasting Report, Lead Optimization: A Reinvention of the Process, examines in detail how to successfully integrate intelligent lead optimization library design and synthesis, advanced screening technologies, and early involvement of in vivo testing. The Report discusses cutting-edge methods, such as computational ADME/Tox, cell-based systems, pharmacogenomics, and metabonomics, along with several case studies in lead optimization. In addition, this Report reviews companies that supply lead optimization tools/services plus assesses aspects of patenting, economics, and regulatory affairs where considerations impacting lead optimization are important.

This Report Will Help You to:

• Discover the five main factors driving the redefinition of the lead optimization process through an in-depth review of each.
• Learn effective data management and visualization resolutions via a review of key strengths of specific informatics software available as turn-key solutions.
• Obtain an all-encompassing picture of lead optimization via a thorough examination of intellectual property issues, regulatory affairs, and manufacturing obstacles influencing the process.
• Identify the most promising lead compounds with an assessment of emerging technologies that are adapting pre-established criteria to target development.
• Recognize often neglected matters in lead optimization - synthesis economics, patenting, and regulatory affairs - from an evaluation of their importance and affect on the process.
• In order to recognize potential solutions get a first-hand account of successful approaches to lead optimization from four descriptive case studies.
• Look inside 10 companies that are pioneering of today's lead discovery and optimization through a complete discussion of their product pipelines, alliances, business strategies, and more.

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