Hydroxytriamides as potent gamma-secretase inhibitors

C V C Prasad; Owen B Wallace; Jeffrey W Noonan; Charles P Sloan; Wai Lau; Shikha Vig; Michael F Parker; David W Smith; Steven B Hansel; Craig T Polson; Donna M Barten; Kevin M Felsenstein; Susan B Roberts

doi:10.1016/j.bmcl.2004.01.086

Hydroxytriamides as potent gamma-secretase inhibitors

Bioorg Med Chem Lett. 2004 Apr 19;14(8):1917-21. doi: 10.1016/j.bmcl.2004.01.086.

Authors

C V C Prasad¹, Owen B Wallace, Jeffrey W Noonan, Charles P Sloan, Wai Lau, Shikha Vig, Michael F Parker, David W Smith, Steven B Hansel, Craig T Polson, Donna M Barten, Kevin M Felsenstein, Susan B Roberts

Affiliation

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. prasad.chaturvedula@bms.com

PMID: 15050627
DOI: 10.1016/j.bmcl.2004.01.086

Abstract

Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.

MeSH terms

Amides / chemical synthesis
Amides / pharmacology*
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
Drug Evaluation, Preclinical
Endopeptidases / drug effects*
Mice
Mice, Transgenic
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Amides
Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
Bace1 protein, mouse