Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
Crane
Sheldon N
SN
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada, H9H 3L1. sheldon_crane@merck.com
Black
W Cameron
WC
Palmer
James T
JT
Davis
Dana E
DE
Setti
Eduardo
E
Robichaud
Joel
J
Paquet
Julie
J
Oballa
Renata M
RM
Bayly
Christopher I
CI
McKay
Daniel J
DJ
Somoza
John R
JR
Chauret
Natalie
N
Seto
Carmai
C
Scheigetz
John
J
Wesolowski
Greg
G
Massé
Frederic
F
Desmarais
Sylvie
S
Ouellet
Marc
M
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006207:Half-Life; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D003510:Cyclohexanes; C508997:N-(cyanomethyl)-5,5-dichloro-(4'-(methylthio)-1,1'-biphenyl-2-yl)cyclohexanecarboxamide; D000607:Aminoacetonitrile; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat