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

  • J Med Chem. 2017 Jul 13;60(13):5933-5939. doi: 10.1021/acs.jmedchem.7b00650.
Timothy B Durham  1 ,  Jothirajah Marimuthu  1 ,  James L Toth  1 ,  Chin Liu  1 ,  Lisa Adams  1 ,  Daniel R Mudra  1 ,  Craig Swearingen  1 ,  Chaohua Lin  1 ,  Mark G Chambers  1 ,  Kannan Thirunavukkarasu  1 ,  Michael R Wiley  1
Affiliations
  • 1. Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
PMID: 28613895 DOI: 10.1021/acs.jmedchem.7b00650
Abstract

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.

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