含鉛化合物之最佳化趨勢

Abstract

Lead Optimization Strategies: Future developments, threats and opportunities for big pharma, specialty pharma and biotech

The pharmaceutical industry has undergone considerable consolidation during the last 20 years as companies attempt to maintain double-digit sales growth and shareholder value. Strategic mergers and acquisitions have resulted in companies revitalizing their drug pipelines to replace blockbuster drugs that face patent expiration. In many cases, whilst mergers cause a period of less productive transition, significant cost-savings can be reaped and overheads reduced. However, more and more companies are resorting to streamlining their internal programs, both pre-clinical and clinical, to improve productivity and the cost-effectiveness of bringing drugs to the market as well as in-licensing late-stage products and outsourcing screening programs which may be less economical to entertain in-house.

Table of Contents

Executive Summary

• The importance of lead optimization
• Traditional big pharma strategies
• Alternative strategies used by specialty pharma and biotech
• Future developments in lead optimization
• Commercial threats and opportunities

Chapter 1 The importance of lead optimization

• Summary
• Introduction
• Current issues facing the pharmaceutical industry
• Introduction to lead optimization
  • Hit generation
  • Lead identification
  • Lead optimization
  • Lead optimization in the R&D process
  • Time and costs associated with lead optimization
• Commercial and clinical importance of lead optimization
• Lead optimization strategies
  • Traditional big pharma strategies
  • Alternative strategies used by specialty pharma and biotech
  • Differences in strategy

Chapter 2 Traditional big pharma strategies

• Summary
• Introduction
• A typical screening cascade
• Key strategic components in lead optimization
  • Team organization for lead optimization
    • Medicinal chemistry functionality
  • Sources of hits and leads
    • Proprietary collections
    • Commercial non-exclusive libraries
    • Natural products
    • Academic groups
    • Advantages and disadvantages of hit sources
  • Improving the quality of compound collections
    • Case study 1: AstraZeneca
    • Case study 2: GSK
  • Setting the criteria for hits, leads and candidate drugs
• Key technologies involved in lead optimization
  • HTS technologies
  • NMR
  • Utility of modeling in lead optimization
    • In silico modeling
    • In vitro modeling
  • Computational chemistry
    • Virtual screening
    • Library design
  • HT protein crystallography
  • Application of molecular biology in lead optimization
  • ADMET screening
    • The role of DMPK in lead optimization
    • Metabolism and covalent binding
    • Toxicity
    • Assays for assessing toxicity
  • HT chemistry
    • Preparative LC-MS chromatography
    • Supercritical Fluid Chromatography (SFC)
• Outsourcing lead optimization
• Weaknesses of the traditional lead optimization model
  • Sequential data gathering
  • Single compound synthesis
  • Animal models
• Conclusions

Chapter 3 Alternative strategies used by specialty pharma & biotech

• Summary
• Introduction
• Alternative lead optimization strategies
• Mimicking big pharma cascades
  • Polypharmacology
• Short/partial screening cascades
  • Case Study: ArQule
• Computational approaches
  • Case study: Locus Pharmaceuticals
• Alternative approaches to screening
• HT crystallography
• Nanotechnology
  • Scanning probe microscopy
  • Nanoparticle formulation
• Outsourcing lead optimization
• Lessons from specialty pharma/biotech strategies
• Conclusions

Chapter 4 Future developments in lead optimization

• Summary
• Introduction
• Key improvement opportunities
• Reductions in time
  • In silico models
• Producing fewer compounds of higher quality more efficiently
  • Cheminformatics
• Bridging the chemistry and target space gap
• Miniaturization of chemistry
• More efficient screening cascades
  • Systems biology
  • Zebrafish model
• Reducing high attrition rates during lead optimization
  • The 'omic revolution: transforming drug discovery
  • Technology developments
• Lead optimization, 2010-2015
• Conclusions

Chapter 5 Commercial threats and opportunities

• Summary
• Introduction
  • Threats
  • Opportunities
• Commercial threats
  • Industry consolidation
  • Increased drug safety requirements
  • Avoidance of untested innovative new technologies
  • Drive towards lower risk "me too" drugs
• Commercial opportunities
  • The genomic revolution
  • Changes to orphan drug legislation
  • Changes in regulatory guidelines: Biomarkers helping to improve the chance
  • of new drug approvals
  • Combinatorial biomarkers aiding efficiency within the D&D process
  • In- and out-Licensing opportunities to create new revenues streams for all
  • players within the industry
• Conclusions

Chapter 6 Appendix

• Abbreviations
• References
• Index