Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
Ruminski, Peter G.,Massa, Mark,Strohbach, Joseph,Hanau, Cathleen E.,Schmidt, Michelle,Scholten, Jeffrey A.,Fletcher, Theresa R.,Hamper, Bruce C.,Carroll, Jeffery N.,Shieh, Huey S.,Caspers, Nicole,Collins, Brandon,Grapperhaus, Margaret,Palmquist, Katherine E.,Collins, Joe,Baldus, John E.,Hitchcock, Jeffrey,Kleine, H. Peter,Rogers, Michael D.,McDonald, Joseph,Munie, Grace E.,Messing, Dean M.,Portolan, Silvia,Whiteley, Laurence O.,Sunyer, Teresa,Schnute, Mark E.
p. 313 - 327
(2016/01/29)
PYRIMIDINE AND PYRIDINE DERIVATIVES AND THEIR PHARMACEUTICAL USE AND COMPOSITIONS
The prsent invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds as anti-inflammatory agents.
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Page/Page column 153-154
(2009/03/07)
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