Advances in Lead Optimization Accelerating Drug Discovery and Development

Critical Issues in Drug Discovery and Development Are Evaluated in This Report:

New approaches to performing lead optimization earlier, and parallelizing lead optimization and target validation.

Advances in the use of assays to reveal drugs that act by many pathways, as well as drug-drug interactions.

Applications of in vitro and in silico methods to predict in vivo ADMET parameters.

Efforts to address toxicity and metabolic instability, and to make poor candidates "fail faster."

Overview:

Advances in Lead Optimization Accelerating Drug Discovery and Development is a new Cambridge Healthtech Institute (CHI) report that evaluates the many efforts that are under way to make lead optimization less time-consuming and more linear. Fueled by the need to bring down the cost of drug discovery and development, a major shift is occurring in how pharmaceutical companies evaluate drug leads. Whereas researchers used to begin by looking at affinity and potency, a genomics/informatics-based research culture is growing and starting to impinge on the classical mode. Companies are now concentrating on determining potential drugs leads' ADMET (absorption, distribution, metabolism, excretion, and toxicological) properties and manufacturability. 

Early attrition of poor drug candidates is central to the new drug discovery paradigm. This report examines the ways in which new technologies can contribute to early attrition. The major trend in lead optimization is the movement toward in silico and high-throughput in vitro approaches. Computational methods can be applied to chemical structures to predict ADMET properties even before the compound is synthesized so that only favorable compounds need be synthesized for screening. Whole cells are also increasingly being used in high-content screening mode to provide selectivity information along with other valuable data concerning the effects of compounds on cell function. Another area of growing impact involves the use of cells equipped with reporter gene constructs for high-throughput analysis of the expression of specific, predetermined genes in response to compound administration. New approaches for predicting toxicity are also examined in this report, particularly the efforts of some groups to develop better animal model systems and to look at ways to introduce these assays earlier in the process. 

In the race to market, companies that provide technologies that go beyond simple data generation to providing knowledge that drives informed decisions will be the most successful. This report is crucial reading for pharmaceutical executives as they seek means to accelerate drug discovery while reducing costs in order to meet their business goals. 

Thought Leaders Interviewed for This Report:

Jim Blake, Array BioPharma; Doug Dolginow, Gene Logic Inc.; Steven Hall, Serenex; Edward E. Hodgkin, Tripos; John Kozarich, ActivX Biosciences; Albert P. Li, PHASE-1 Molecular Toxicology Inc.; Douglas A. Livingston, Discovery Partners International; Jeffrey Voss, Abbott Bioresearch Center 

Publication date/length: February 2003, 120 pages.

Publisher: Cambridge Healthtech Institute 

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