Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis

Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]
M J JanuszV Patel

Abstract

Hydroxamic-and carboxylic-acid based matrix metalloproteinase inhibitors (MMPIs) were compared for their potency against various MMPs, pharmacodynamic properties and in vivo efficacy in a model of cartilage degeneration. The MMPIs were evaluated for their ability to inhibit human MMPs using the quenched fluorescence assay. The ability of the MMPIs to inhibit the degeneration of the knee joint was evaluated in rats injected intraarticularly with iodoacetate. The amount of MMPI in the plasma and cartilage was determined using liquid chromatography/mass spectrometry/mass spectrometry (LC/ MS/MS). Plasma protein binding was measured by ultrafiltration and unbound MMPI was quantitated using HPLC. The hydroxamic acid based inhibitor PGE-3321996 and the carboxylic acids PGE-2909492 and PGE-6292544 were potent MMP-13 inhibitors, but only the hydroxamic acid PGE 3321996 demonstrated significant inhibition of knee degeneration in the rat iodoacetate model. Both of the carboxylic acids demonstrated superior pharmacokinetic properties and established much higher plasma concentrations than the hydroxamic acid. However, neither of the carboxylic acids was detectable in the cartilage, whereas, the hydroxamic acid was present in both the carti...Continue Reading

Citations

Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·J I LevinJ D Albright
May 2, 2013·Journal of Medicinal Chemistry·Yonghao JinQing-Xiang Amy Sang
Oct 3, 2015·Expert Opinion on Investigational Drugs·Kang WangChanghai Ding
Dec 14, 2007·Expert Opinion on Therapeutic Targets·Andrew D RowanJennifer M Milner
Dec 23, 2017·Rheumatology·Zhengping HuangShirley Pei-Chun Yu

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