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).
Arthritis and Bone Metabolism Research, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Lauren G
LG
Monovich
Ruben A
RA
Tommasi
Roger A
RA
Fujimoto
Vincent
V
Blancuzzi
Kirk
K
Clark
Wendy D
WD
Cornell
Robert
R
Doti
John
J
Doughty
James
J
Fang
David
D
Farley
John
J
Fitt
Vishwas
V
Ganu
Ronald
R
Goldberg
Robert
R
Goldstein
Stacey
S
Lavoie
Raviraj
R
Kulathila
William
W
Macchia
David T
DT
Parker
Richard
R
Melton
Elizabeth
E
O'Byrne
Gary
G
Pastor
Theodore
T
Pellas
Elizabeth
E
Quadros
Noela
N
Reel
Dennis M
DM
Roland
Yumi
Y
Sakane
Hem
H
Singh
Jerry
J
Skiles
Joseph
J
Somers
Karen
K
Toscano
Andrew
A
Wigg
Siyuan
S
Zhou
Lijuan
L
Zhu
Wen-Chung
WC
Shieh
Song
S
Xue
Leslie W
LW
McQuire
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