活潑化的先導化合物製造：崛起的技術及策略

活潑化的先導化合物製造：崛起的技術及策略 是由出版商Business Insights在2009年06月所出版的。 這份英文市場調查報告書包含161 pages 價格從美金3835起跳。

簡介

目錄

Abstract

The number of approvals for new drugs and biologics has fallen steadily in recent years, despite increasing R&D expenditure. Cost effective and innovative approaches to drug discovery and development have therefore become particularly important to ensure shareholder value. Improvements to the lead generation process are a key initiative for company' s aiming to avoid expensive compound failures in the latter stages of the drug discovery process. ‘Accelerating Lead Generation: Emerging technologies and strategies' is a new report published by Business Insights that provides an in-depth examination of state-of-the-art technologies for lead generation. This report assesses the potential of new and emerging technologies for improving the quality of drug candidates entering clinical research, and reviews the benefits associated with different approaches to lead generation, including high throughput screening, fragment based drug discovery and virtual screening. The lead generation strategies adopted by leading pharma companies are evaluated to provide strategic recommendations for success, and the trends that are shaping the future acceleration of lead generation are identified.

Table of Contents

Executive Summary

• Introduction
• Identifying hits: library design, virtual screening and fragment based drug discovery
• Innovations in biological assay development
• ADME and toxicology in lead generation
• Lead generation strategies in the pharma industry
• R&D models, innovation and future success of lead generation

Chapter 1 - Introduction

• The drug discovery process: defining lead generation
• Hit finding and verification
• Hit optimization
• Lead optimization
• Criteria for potential lead compounds
  • Chemistry
  • Pharmacology
  • Absorption, Metabolism, Excretion, Distribution (ADME) and Toxicity

Chapter 2 - Identifying hits: library design, virtual screening and fragment based drug discovery

• Summary
• Introduction
• Hit to lead - identifying possible structures
• Compound selection
• Physiochemical properties
• Chemical optimization and modification of hits
  • Engineering novelty

• Beyond HTS - alternative methods for identifying hits

• Fragment-based drug discovery
• Companies involved in FBDD
  • Case study: deCODE chemistry & biostructures Inc.
  • Case study: Zenobia Therapeutics
• Can FBDD generate successful new drugs?
• Technology improvements driving FBDD
  • Improving x-ray crystallography
  • Improvements in NMR spectroscopy for FBDD
  • High concentration biological assays
  • Improving biophysical methods
  • Improving fragment library design
  • Chemistry-based methods
• HTS vs FBDD

• Virtual screening
• Target based virtual screening
  • Case study: Epix Pharmaceuticals'
• When to use virtual screening
• Target based virtual screening: challenges
• Ligand based screening
• Commercial virtual screening platforms

• Conclusions

Chapter 3 - Innovations in biological assay development

• Summary
• Introduction

• Improving high throughput screening
• Identifying valid hits
• A quantitative approach to primary screening
  • Compound management and quality assessment
  • Dispensing
• Informatics and data analysis

• Improving in vitro assays for HTS
• Surface plasmon resonance
• Isothermal titration calorimetry and nanocalorimetry
  • Back-Scattering Interferometry
• Differential scanning fluorimetry
• High throughput Mass Spectrometry
• Bio-layer interferometry

• Innovations in cell-based assay technology
• Automated confocal microscopy methods
• Flow cytometry
• Laser scanning cytometry
• Label-free cell-based screens
  • Photonic crystal biosensors
  • Dynamic mass redistribution
  • Impedance-based whole cell biosensors
• Other cell-based assays
  • Reverse arrays
  • Enzyme Fragment Complementation
• HCS and SAR
• Novel cell types and cultures

• In vivo methods in lead generation
• Zebrafish

• Whole animal imaging and microscopy

• Conclusions

Chapter 4 - ADME and toxicology in lead generation

• Summary
• Introduction

• Assessing ADME characteristics
• Oral absorption
• P-Glycoprotein interactions
• Plasma protein binding
• Clearance
• Metabolic stability
• Selectivity and off-target effects
• Solubility

• Toxicology at the lead generation stage
• In silico structure-toxicity relationships
• Chemoinformatic methods
• Toxicogenomics
• High content screening
• Zebrafish
• Whole animal imaging
• Determining mutagenic and clastogenic potential
• Measuring HERG liability
• Investigating CYP inhibition and induction

• Conclusions

Chapter 5 - Lead generation strategies in the pharma industry

• Summary
• Introduction
• Lead generation teams

• Case studies
• Bayer
• Boehringer Ingelheim
• Millennium Pharmaceuticals (Takeda)

• Conclusions

Chapter 6 - R&D models, innovation & future success of lead generation

• Summary
• Introduction

• R&D models: influence on lead generation
• R&D models
• Outsourcing and offshoring
• Dealing with academia
• Pharma collaboration - ‘Co-opetition'

• Innovation and the future
• Targets and HTS
• Focus on RNA
• Focus on lead optimization
• Nanochemistry - returning chemistry to its central role in drug discovery

• Lead generation now and in the future

Chapter 7 - Appendix

• Primary research methodology Acknowledgments
• Glossary
• Index
• Bibliography

List of Figures

• Figure 1.1: Pharma industry productivity decline (1999-2008)
• Figure 1.2: Patent losses occurring between 2008-2014
• Figure 1.3: The drug discovery process
• Figure 1.4: Example of a lead generation workflow
• Figure 1.5: Technologies involved in lead generation
• Figure 2.6: Use of structural information in structure-based drug design
• Figure 2.7: Examples of the chemical structures of compounds discovered using FBDD
• Figure 2.8: ZoBio' s target immobilized NMR spectroscopy method for fragment-based drug discovery
• Figure 3.9: Areas of innovation in high throughput screening
• Figure 3.10: Acoustic droplet ejection
• Figure 3.11: Attributes required of software for HTS data storage and analysis
• Figure 3.12: Kinetic characterization of 5 lead series using SPR (Biacore)
• Figure 3.13: Bio-Layer Interferometry from ForteBio
• Figure 3.14: Advantages of cell-based screening in HTS
• Figure 3.15: Principle of detection: cell based assays with the Epic system from Corning
• Figure 3.16: Principle of the EFC assay for a biochemical target: HitHunter from DiscoveRx
• Figure 4.17: ADME and toxicology data available in high throughput assays
• Figure 4.18: The Safety Intelligence Program from BioWisdom
• Figure 4.19: Examples of assertions in the Safety Intelligence Program from BioWisdom
• Figure 4.20: A typical toxicogenomics workflow in the pharma industry
• Figure 5.21: Key innovations in lead generation technologies
• Figure 5.22: Key activities of medicinal chemists during lead generation
• Figure 5.23: ADME-Tox traffic light criteria in use at Bayer
• Figure 5.24: Discovery-Assays-By-Stage paradigm of Millennium Pharmaceuticals
• Figure 6.25: The microreactor-based lead discovery system

List of Tables

• Table 2.1: Fragment-based drug discovery: the pros and cons
• Table 2.2 Techniques used to assess fragment binding for FBDD
• Table 2.3: Examples of companies with product pipelines derived from FBDD
• Table 2.4: Examples of compounds discovered using FBDD
• Table 2.5: Rule of Three criteria for a fragment library
• Table 2.6: Examples of companies offering fragment libraries and collections for FBDD
• Table 2.7: Examples of companies offering software for virtual screening
• Table 3.8: Examples of companies providing software for HTS information storage and analysis
• Table 3.9: Emerging technologies for high throughput screening
• Table 3.10: A comparison of free-solution, label-free molecular interaction techniques
• Table 3.11: Examples of recent collaborations between stem cell companies and big pharma for the use of stem cells in drug discovery research
• Table 3.12: Advantages and disadvantages of zebrafish for compound screening
• Table 3.13: Companies offering zebrafish screening products and services
• Table 3.14: Advantages of molecular imaging of whole animals for preclinical studies
• Table 3.15: Half lives of important positron emitting isotopes
• Table 4.16: Examples of contract laboratories offering HCA cytotoxicity screening
• Table 4.17: Examples of higher throughput or miniaturized versions of the Ames test
• Table 6.18: Recent examples of academic drug discovery funding by big pharma

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