Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 4: Lead Optimization in Drug Discovery

Craig W. Lindsley

David Weaver

Thomas M. Bridges

J. Phillip Kennedy

Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Departments of Pharmacology and Chemistry, Nashville, Tennessee

Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Department of Pharmacology, Nashville, Tennessee

Vanderbilt University, Department of Chemistry, Nashville, Tennessee

Lead optimization in drug discovery has changed significantly over the years and no longer is fragmented into separate hit-to-lead and lead optimization phases. Chemical lead optimization from high-throughput screening (HTS) to clinical candidate identification is now one seamless process that draws on new technologies for accelerated synthesis, purification, and screening of directed, iterative compound libraries. Advances In high-throughput screening technologies allow detection of new allosteric modes of target modulation, which provides new chemotypes and target opportunities. With the incorporation of drug metabolism and pharmacokinetics (DMPK) inputs early in the lead optimization work flow, molecules are not optimized solely for target potency and selectivity. Moreover, at the time of writing, “closed-loop” work flows are in place such that synthesis and primary screening operate on a 1-week turnaround for up to 48 compounds/week with DMPK data cycling every other week to guide compound design, which provides expedited timelines ...