Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K.
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
Palmer
James T
JT
Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080, USA. jim.palmer@celera.com
Bryant
Clifford
C
Wang
Dan-Xiong
DX
Davis
Dana E
DE
Setti
Eduardo L
EL
Rydzewski
Robert M
RM
Venkatraman
Shankar
S
Tian
Zong-Qiang
ZQ
Burrill
Leland C
LC
Mendonca
Rohan V
RV
Springman
Eric
E
McCarter
John
J
Chung
Tobee
T
Cheung
Harry
H
Janc
James W
JW
McGrath
Mary
M
Somoza
John R
JR
Enriquez
Philip
P
Yu
Z Walter
ZW
Strickley
Robert M
RM
Liu
Liang
L
Venuti
Michael C
MC
Percival
M David
MD
Falgueyret
Jean-Pierre
JP
Prasit
Peppi
P
Oballa
Renata
R
Riendeau
Denis
D
Young
Robert N
RN
Wesolowski
Gregg
G
Rodan
Sevgi B
SB
Johnson
Colena
C
Kimmel
Donald B
DB
Rodan
Gideon
G
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D015415:Biomarkers / Q000652:urine; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001862:Bone Resorption / Q000652:urine; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002417:Cattle; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001549:Benzamides; D015415:Biomarkers; D050071:Bone Density Conservation Agents; C507712:CRA 013783; D009570:Nitriles; D013844:Thiazoles; D003094:Collagen; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat