2. Academic Validation
  3. Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies

Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies

  • J Med Chem. 2006 May 18;49(10):2898-908. doi: 10.1021/jm0510979.
Tina Morwick 1,  Angela Berry,  Janice Brickwood,  Mario Cardozo,  Katrina Catron,  Molly DeTuri,  Jonathan Emeigh,  Carol Homon,  Matt Hrapchak,  Stephen Jacober,  Scott Jakes,  Paul Kaplita,  Terence A Kelly,  John Ksiazek,  Michel Liuzzi,  Ronald Magolda,  Can Mao,  Daniel Marshall,  Daniel McNeil,  Anthony Prokopowicz 3rd,  Christopher Sarko,  Erika Scouten,  Cynthia Sledziona,  Sanxing Sun,  Jane Watrous,  Jiang Ping Wu,  Charles L Cywin
Affiliations

Affiliation

  • 1 Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06801-0368, USA. tmorwick@rdg.boeringer-ingelheim.com
PMID: 16686533 DOI: 10.1021/jm0510979
Abstract

High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory Enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for Enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.

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