Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.
The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.
Thompson
Lorin A
LA
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. lorin.thompson@bms.com
Liauw
Ann Y
AY
Ramanjulu
Mercy M
MM
Kasireddy-Polam
Padmaja
P
Mercer
Stephen E
SE
Maduskuie
Thomas P
TP
Glicksman
Marcie
M
Roach
Arthur H
AH
Meredith
Jere E
JE
Liu
Rui-Qin
RQ
Combs
Andrew P
AP
Higaki
Jeffrey N
JN
Cordell
Barbara
B
Seiffert
Dietmar
D
Zaczek
Robert C
RC
Robertson
David W
DW
Olson
Richard E
RE
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002209:Caprolactam / Q000031:analogs & derivatives / Q000737:chemistry*; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000737:chemistry / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry*
D004791:Enzyme Inhibitors; D013386:Succinates; D002209:Caprolactam; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human