{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:23:29Z","timestamp":1791487409062,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,6,29]],"date-time":"2009-06-29T00:00:00Z","timestamp":1246233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2009,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad\u2010spectrum MMP inhibitors developed for this purpose has been restricted by dose\u2010limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP\u201013 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)\u2013induced OA was implemented for assessing the effects of MMP\u201013 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP\u201013 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP\u201013 inhibitors have the joint toxicity associated with broad\u2010spectrum MMP inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A number of non\u2013hydroxamic acid\u2013containing compounds that showed a high degree of potency for MMP\u201013 and selectivity against other MMPs were designed and synthesized. Steady\u2010state kinetics experiments and Lineweaver\u2010Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1\u20100635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1\u20100635 demonstrated nonexclusive binding. ALS 1\u20100635 inhibited bovine articular cartilage degradation in a dose\u2010dependent manner (48.7% and 87.1% at 500 n<jats:italic>M<\/jats:italic> and 5,000 n<jats:italic>M<\/jats:italic>, respectively) and was effective in inhibiting interleukin\u20101\u03b1\u2013 and oncostatin M\u2013induced C1,C2 release in human OA cartilage cultures. ALS 1\u20100635 modulated cartilage damage in the rat MIA model (mean \u00b1 SEM damage score 1.3 \u00b1 0.3, versus 2.2 \u00b1 0.4 in vehicle\u2010treated animals). Most significantly, when treated twice daily with oral ALS 1\u20100635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The compounds investigated in this study represent a novel class of MMP\u201013 inhibitors. They are mechanistically distinct from previously reported broad\u2010spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP\u201013 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease\u2010modifying osteoarthritis drugs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.24629","type":"journal-article","created":{"date-parts":[[2009,6,29]],"date-time":"2009-06-29T15:05:41Z","timestamp":1246287941000},"page":"2008-2018","source":"Crossref","is-referenced-by-count":148,"title":["A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models"],"prefix":"10.1002","volume":"60","author":[{"given":"Vijaykumar M.","family":"Baragi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Becher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison 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