Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors

Xiaocong M Ye; Andrei W Konradi; Jenifer Smith; Ying-Zi Xu; Darren Dressen; Albert W Garofalo; Jennifer Marugg; Hing L Sham; Anh P Truong; Jacek Jagodzinski; Michael Pleiss; Hongbin Zhang; Erich Goldbach; John-Michael Sauer; Elizabeth Brigham; Michael Bova; Guriqbal S Basi

doi:10.1016/j.bmcl.2010.02.039

Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2195-9. doi: 10.1016/j.bmcl.2010.02.039. Epub 2010 Feb 13.

Authors

Xiaocong M Ye¹, Andrei W Konradi, Jenifer Smith, Ying-Zi Xu, Darren Dressen, Albert W Garofalo, Jennifer Marugg, Hing L Sham, Anh P Truong, Jacek Jagodzinski, Michael Pleiss, Hongbin Zhang, Erich Goldbach, John-Michael Sauer, Elizabeth Brigham, Michael Bova, Guriqbal S Basi

Affiliation

¹ Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States. [email protected]

PMID: 20207136
DOI: 10.1016/j.bmcl.2010.02.039

Abstract

Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.

MeSH terms

Alzheimer Disease / drug therapy
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism*
Animals
Humans
Mice
Models, Molecular
Piperidines / chemistry*
Piperidines / pharmacology*
Piperidines / therapeutic use
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use

Substances

Piperidines
Sulfonamides
Amyloid Precursor Protein Secretases