Build-Couple-Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity

J Med Chem. 2022 Aug 25;65(16):11322-11339. doi: 10.1021/acs.jmedchem.2c00897. Epub 2022 Aug 9.

Abstract

High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a "build-couple-transform" paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build-couple-transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • High-Throughput Screening Assays*
  • Small Molecule Libraries* / chemistry

Substances

  • Small Molecule Libraries