2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Jan 14;59(1):313-27. doi: 10.1021/acs.jmedchem.5b01434.
Peter G Ruminski,  Mark Massa,  Joseph Strohbach,  Cathleen E Hanau,  Michelle Schmidt,  Jeffrey A Scholten,  Theresa R Fletcher,  Bruce C Hamper,  Jeffery N Carroll,  Huey S Shieh,  Nicole Caspers,  Brandon Collins,  Margaret Grapperhaus,  Katherine E Palmquist,  Joe Collins,  John E Baldus,  Jeffrey Hitchcock,  H Peter Kleine,  Michael D Rogers,  Joseph McDonald,  Grace E Munie,  Dean M Messing 1,  Silvia Portolan 1,  Laurence O Whiteley 2,  Teresa Sunyer,  Mark E Schnute
Affiliations

Affiliations

  • 1 Pharmacokinetics, Dynamics, and Metabolism, Pfizer , 700 North Main Street, Cambridge, Massachusetts 02139, United States.
  • 2 Drug Safety, Pfizer , 1 Burtt Road, Andover, Massachusetts 01810, United States.
PMID: 26653735 DOI: 10.1021/acs.jmedchem.5b01434
Abstract

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.

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