Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13.
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).
Monovich
Lauren G
LG
Arthritis and Bone Metabolism Research, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Tommasi
Ruben A
RA
Fujimoto
Roger A
RA
Blancuzzi
Vincent
V
Clark
Kirk
K
Cornell
Wendy D
WD
Doti
Robert
R
Doughty
John
J
Fang
James
J
Farley
David
D
Fitt
John
J
Ganu
Vishwas
V
Goldberg
Ronald
R
Goldstein
Robert
R
Lavoie
Stacey
S
Kulathila
Raviraj
R
Macchia
William
W
Parker
David T
DT
Melton
Richard
R
O'Byrne
Elizabeth
E
Pastor
Gary
G
Pellas
Theodore
T
Quadros
Elizabeth
E
Reel
Noela
N
Roland
Dennis M
DM
Sakane
Yumi
Y
Singh
Hem
H
Skiles
Jerry
J
Somers
Joseph
J
Toscano
Karen
K
Wigg
Andrew
A
Zhou
Siyuan
S
Zhu
Lijuan
L
Shieh
Wen-Chung
WC
Xue
Song
S
McQuire
Leslie W
LW
D000818:Animals; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D024043:Collagen Type II / Q000378:metabolism; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
C541702:4-(carboxy-(5-(4'-ethoxyphenyl)thiophene-2-sulfonylamino)methyl)piperidine-1-carboxylic acid isopropyl ester; D024043:Collagen Type II; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines; D011480:Protease Inhibitors; D011509:Proteoglycans; D013449:Sulfonamides