2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Pissarnitski
Dmitri A
DA
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. Dmitri.Pisaarnitski@spcorp.com
Asberom
Theodros
T
Bara
Thomas A
TA
Buevich
Alex V
AV
Clader
John W
JW
Greenlee
William J
WJ
Guzik
Henry S
HS
Josien
Hubert B
HB
Li
Wei
W
McEwan
Michael
M
McKittrick
Brian A
BA
Nechuta
Terry L
TL
Parker
Eric M
EM
Sinning
Lisa
L
Smith
Elizabeth M
EM
Song
Lixin
L
Vaccaro
Henry A
HA
Voigt
Johannes H
JH
Zhang
Lili
L
Zhang
Qi
Q
Zhao
Zhiqiang
Z
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010880:Piperidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases