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

Xiaocong M Ye; 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

doi:10.1016/j.bmcl.2012.12.039

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. Epub 2012 Dec 21.

Affiliation

¹ Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA. mxcye@hotmail.com

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.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Animals
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Mice
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Bridged Bicyclo Compounds, Heterocyclic
Pyrazoles
Sulfonamides
Amyloid Precursor Protein Secretases