Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors.
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.
Bekkali
Younes
Y
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. ybekkali@rdg.boehringer-ingelheim.com
Thomson
David S
DS
Betageri
Raj
R
Emmanuel
Michel J
MJ
Hao
Ming-Hong
MH
Hickey
Eugene
E
Liu
Weimin
W
Patel
Usha
U
Ward
Yancey D
YD
Young
Erick R R
ER
Nelson
Richard
R
Kukulka
Alison
A
Brown
Maryanne L
ML
Crane
Kathy
K
White
Della
D
Freeman
Dorothy M
DM
Labadia
Mark E
ME
Wildeson
Jessi
J
Spero
Denice M
DM
D020134:Catalytic Domain; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D009570:Nitriles / Q000737:chemistry* / Q000145:classification; D010455:Peptides / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship
D004151:Dipeptides; D009570:Nitriles; D010455:Peptides; D010880:Piperidines; D011759:Pyrrolidines; C032727:piperidine; D002403:Cathepsins; C028217:cathepsin S; C032519:pyrrolidine