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J Med Chem. 2017 Jul 13;60(13):5933-5939. doi: 10.1021/acs.jmedchem.7b00650. Epub 2017 Jun 29.

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

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1
Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.

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.

PMID:
28613895
DOI:
10.1021/acs.jmedchem.7b00650
[Indexed for MEDLINE]

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