Discovery of sulfonamide-pyrazole gamma-secretase inhibitors

Matthew N Mattson; Martin L Neitzel; David A Quincy; Christopher M Semko; Albert W Garofalo; Pamela S Keim; Andrei W Konradi; Michael A Pleiss; Hing L Sham; Elizabeth F Brigham; Erich G Goldbach; Hongbin Zhang; John-Michael Sauer; Guriqbal S Basi

doi:10.1016/j.bmcl.2010.02.050

Discovery of sulfonamide-pyrazole gamma-secretase inhibitors

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2148-50. doi: 10.1016/j.bmcl.2010.02.050. Epub 2010 Feb 14.

Authors

Matthew N Mattson¹, Martin L Neitzel, David A Quincy, Christopher M Semko, Albert W Garofalo, Pamela S Keim, Andrei W Konradi, Michael A Pleiss, Hing L Sham, Elizabeth F Brigham, Erich G Goldbach, Hongbin Zhang, John-Michael Sauer, Guriqbal S Basi

Affiliation

¹ Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, CA 94080, United States.

PMID: 20206516
DOI: 10.1016/j.bmcl.2010.02.050

Abstract

Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.

MeSH terms

Alzheimer Disease / drug therapy*
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism*
Animals
Crystallography, X-Ray
Humans
Inhibitory Concentration 50
Models, Molecular
Pyrazoles / chemistry
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*

Substances

Pyrazoles
Sulfonamides
pyrazole
Amyloid Precursor Protein Secretases