Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors

  • Bioorg Med Chem Lett. 2013 Feb 15;23(4):996-1000. doi: 10.1016/j.bmcl.2012.12.039.
Xiaocong M Ye  1 ,  Andrei W Konradi ,  Minghua Sun ,  Shendong Yuan ,  Danielle L Aubele ,  Michael Dappen ,  Darren Dressen ,  Albert W Garofalo ,  Jacek J Jagodzinski ,  Lee Latimer ,  Gary D Probst ,  Hing L Sham ,  David Wone ,  Ying-zi Xu ,  Daniel Ness ,  Elizabeth Brigham ,  Grace T Kwong ,  Chris Willtis ,  George Tonn ,  Erich Goldbach ,  Kevin P Quinn ,  Hongbin H Zhang ,  John-Michael Sauer ,  Michael Bova ,  Guriqbal S Basi
Affiliations
  • 1. Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA. [email protected]
PMID: 23312944 DOI: 10.1016/j.bmcl.2012.12.039
Abstract

Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.