Design and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent gamma-secretase inhibitors.
We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. The in vitro structure-activity relationships of 2 and 3 along with dog pharmacokinetic results are described.
Yang
Michael G
MG
Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. michael.yang@bms.com
Shi
Jian-Liang
JL
Modi
Dilip P
DP
Wells
Jennifer
J
Cochran
Brian M
BM
Wolf
Mark A
MA
Thompson
Lorin A
LA
Ramanjulu
Mercy M
MM
Roach
Arthur H
AH
Zaczek
Robert
R
Robertson
David W
DW
Wexler
Ruth R
RR
Olson
Richard E
RE
D000577:Amides / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003500:Cyclization; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000577:Amides; D001381:Azepines; D053829:Amyloid Precursor Protein Secretases