Discovery of a novel series of Notch-sparing gamma-secretase inhibitors

  • Bioorg Med Chem Lett. 2008 Jul 15;18(14):4232-6. doi: 10.1016/j.bmcl.2008.05.064.
Anthony Kreft  1 ,  Boyd Harrison ,  Suzan Aschmies ,  Kevin Atchison ,  David Casebier ,  Derek C Cole ,  George Diamantidis ,  John Ellingboe ,  Diane Hauze ,  Yun Hu ,  Donna Huryn ,  Mei Jin ,  Dennis Kubrak ,  Peimin Lu ,  Joseph Lundquist ,  Charles Mann ,  Robert Martone ,  William Moore ,  Aram Oganesian ,  Alex Porte ,  Dave R Riddell ,  June Sonnenberg-Reines ,  Joseph R Stock ,  Shaiu-Ching Sun ,  Erik Wagner ,  Kevin Woller ,  Zheng Xu ,  Hua Zhou ,  J Steven Jacobsen
Affiliations
  • 1. Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. [email protected]
PMID: 18556202 DOI: 10.1016/j.bmcl.2008.05.064
Abstract

Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity.