3 years ago

A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose

A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose
Michael R. Wiley, Jothirajah Marimuthu, Kannan Thirunavukkarasu, Chaohua Lin, Daniel R. Mudra, Lisa Adams, James L. Toth, Timothy B. Durham, Craig Swearingen, Mark G. Chambers, Chin Liu
Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00650

DOI: 10.1021/acs.jmedchem.7b00650

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