Design, synthesis, and structure-activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline gamma-secretase inhibitors

Anh P Truong; Danielle L Aubele; Gary D Probst; Martin L Neitzel; Chris M Semko; Simeon Bowers; Darren Dressen; Roy K Hom; Andrei W Konradi; Hing L Sham; Albert W Garofalo; Pamela S Keim; Jing Wu; Michael S Dappen; Karina Wong; Erich Goldbach; Kevin P Quinn; John-Michael Sauer; Elizabeth F Brigham; William Wallace; Lan Nguyen; Susanna S Hemphill; Michael P Bova; Frédérique Bard; Ted A Yednock; Guriqbal Basi

doi:10.1016/j.bmcl.2009.07.092

Design, synthesis, and structure-activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline gamma-secretase inhibitors

Bioorg Med Chem Lett. 2009 Sep 1;19(17):4920-3. doi: 10.1016/j.bmcl.2009.07.092. Epub 2009 Jul 23.

Affiliation

¹ Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA.

PMID: 19660943
DOI: 10.1016/j.bmcl.2009.07.092

Abstract

In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.

MeSH terms

Administration, Oral
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Animals
Drug Design
Mice
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
Pyrazoles / chemistry*
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacology
Structure-Activity Relationship
Sulfonamides / chemistry*

Substances

Protease Inhibitors
Pyrazoles
Quinolines
Sulfonamides
pyrazole
Amyloid Precursor Protein Secretases