Identification of potent and selective MMP-13 inhibitors.
A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.
Wu
Junjun
J
Department of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Rush
Thomas S
TS
Hotchandani
Rajeev
R
Du
Xuemei
X
Geck
Mary
M
Collins
Elisabeth
E
Xu
Zhang-Bao
ZB
Skotnicki
Jerry
J
Levin
Jeremy I
JI
Lovering
Frank E
FE
D000284:Administration, Oral; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001572:Benzofurans / Q000737:chemistry; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D002614:Chelating Agents / Q000737:chemistry; D017364:Collagenases / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism
D000596:Amino Acids; D001572:Benzofurans; D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D015032:Zinc; C105430:benzofuran