Hydroxytriamides as potent gamma-secretase inhibitors.
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.
Prasad
C V C
CV
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. prasad.chaturvedula@bms.com
Wallace
Owen B
OB
Noonan
Jeffrey W
JW
Sloan
Charles P
CP
Lau
Wai
W
Vig
Shikha
S
Parker
Michael F
MF
Smith
David W
DW
Hansel
Steven B
SB
Polson
Craig T
CT
Barten
Donna M
DM
Felsenstein
Kevin M
KM
Roberts
Susan B
SB
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse