4 research outputs found
Conformationally Restricted Peptide Mimetics: The Incorporation of 6,5-Bicyclic Lactam Ring Skeletons into Peptides
APPLICATION OF HMBC AND HMQC-TOCSY NMR METHODS TO ASSIGN THE STRUCTURES OF BICYCLIC-PEPTIDE MIMETICS
Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: Use of a conformation-based hypothesis to facilitate compound design
Discovery of <i>N</i>‑(4-Fluoro-3-methoxybenzyl)-6-(2-(((2<i>S</i>,5<i>R</i>)‑5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)‑2<i>H</i>‑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 <b>43a</b> lacking the previously observed preclinical toxicology at comparable
exposures