Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.
Hu
Yonghan
Y
Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, USA. fhu@wyeth.com
Xiang
Jason S
JS
DiGrandi
Martin J
MJ
Du
Xuemei
X
Ipek
Manus
M
Laakso
Leif M
LM
Li
Jianchang
J
Li
Wei
W
Rush
Thomas S
TS
Schmid
Jean
J
Skotnicki
Jerauld S
JS
Tam
Steve
S
Thomason
Jennifer R
JR
Wang
Qin
Q
Levin
Jeremy I
JI
D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry; D017364:Collagenases / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy*; D051381:Rats; D013379:Substrate Specificity
D001572:Benzofurans; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat