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

Durham, Timothy B; Marimuthu, Jothirajah; Toth, James L; Liu, Chin; Adams, Lisa; Mudra, Daniel R; Swearingen, Craig; Lin, Chaohua; Chambers, Mark G; Thirunavukkarasu, Kannan; Wiley, Michael R

Durham, Timothy B; Marimuthu, Jothirajah; Toth, James L; Liu, Chin; Adams, Lisa; Mudra, Daniel R; Swearingen, Craig; Lin, Chaohua; Chambers, Mark G; Thirunavukkarasu, Kannan; Wiley, Michael R.

Affiliation

Durham TB; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Marimuthu J; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Toth JL; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Liu C; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Adams L; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Mudra DR; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Swearingen C; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Lin C; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Chambers MG; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Thirunavukkarasu K; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Wiley MR; Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.

J Med Chem ; 60(13): 5933-5939, 2017 07 13.

Article de En | MEDLINE | ID: mdl-28613895

ABSTRACT

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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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Arthrose / Antienzymes / Protéine ADAMTS4 / Protéine ADAMTS5 / Hydantoïnes Limites: Animals / Humans / Male Langue: En Journal: J Med Chem Sujet du journal: QUIMICA Année: 2017 Type de document: Article Pays d'affiliation: États-Unis d'Amérique

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