Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

Abstract

Matrix metalloproteinase-13 (MMP-13) plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). The subtle differences between the S1' loop of MMP-13 and that of other MMPs offer a structural base for the design of selective MMP-13 inhibitors to mitigate the unperceived risk associated with inhibiting other MMP isoforms. In this review, we summarize zinc-binding and non-zinc-binding selective MMP-13 inhibitors. The zinc-binding MMP-13 inhibitors contain a small set of zinc-binding groups (ZBGs), including hydroxamic acid, pyrimidinetrione, reversed hydroxamic acid and hydantoin, carboxylic acid, 1,2,4,-triazole, and 1,2,4,-triazolone. The non-zinc-binding MMP-13 inhibitors have different structural scaffolds, including diphenyl ethers, biaryls (aryltetrazoliums, arylfurans, pyrazole-indoles), pyrimidines, and aryl/cycloalkyl-fused pyrimidines. This review provides a systematic overview of recent developments in MMP-13 inhibitors for the treatment of OA, with emphasis on their enzyme inhibitory potency, selectivity, and biological activities, and highlights the various binding modes of typical inhibitors with MMP-13.

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…Since their discovery, MMPs have emerged as an intriguing target in pharmaceutical research . Due to the involvement of members of the MMP family in a multitude of severe diseases, such as cancer, arthritis, chronic obstructive pulmonary disease (COPD), or sepsis, great efforts were taken to modulate MMP activity to possibly treat diseases in which MMP activity is out of balance . Due to side effects evolving from a lack of selectivity and insufficient knowledge about the relevance of the target family in pathological processes, no compound designed as an MMP inhibitor has reached the market so far, and clinical trials have failed .…”

“…[5][6][7][8][9] Due to the involvement of members of the MMP family in am ultitude of severe diseases, such as cancer, [10][11][12][13][14][15][16] arthritis, [17,18] chronic obstructive pulmonary disease (COPD), [19][20][21] or sepsis, [22][23][24][25] great efforts weret aken to modulate MMP activity to possibly treat diseases in which MMP activity is out of balance. [26,27] Due to side effects evolving from al ack of selectivity and insufficient knowledge aboutt he relevance of the target family in pathological processes, no compound designed as an MMP inhibitor has reached the market so far,a nd clinicalt rials have failed. [28] Doxycycline, an antibiotic tetracycline that exhibitso ff-target inhibition of MMP-7a nd MMP-8, is the only compound approved as aM MP inhibitor for the treatment of periodontitis.…”

BST106 Protects against Cartilage Damage by Inhibition of Apoptosis and Enhancement of Autophagy in Osteoarthritic Rats

“…32) Administration of specific MMP-13 inhibitors significantly reduced the severity of the pathology in both human and animal models of OA. 33,34) Resveratrol, a natural antioxidant, reduced MIA-induced pain by inhibiting MMP-13 mRNA expression and inflammatory cytokines in rats. 35) Our previous study showed that GCSB-5, a herbal formulation, protected against articular cartilage destruction by suppressing MMP-2 activity and cyclooxygenase-2 expression in a MIA-induced OA rat model.…”

The Effect of the Prethanol Extract of <b><i>Trifolium pratense</i></b> Leaves on Interleukin-1β-Induced Cartilage Matrix Degradation in Primary Rat Chondrocytes

“…The enhancement of MMP activity in cartilage tissues is caused an imbalance between the catabolism and the anabolism of chondrocytes, which leads to the irreversible degradation of COL2A1 and proteoglycans, essential constituents of the ECM responsible for the protection of articular cartilage and chondrocytes [Goldring et al, 2011;Heinegard and Saxne, 2011]. MMP-3 and MMP-13, in particular, are key players in the catabolic processes of OA, and they decompose aggrecan and COL2A1 which provide elasticity to the cartilage and aid shock relaxation [Wang et al, 2013;Xie et al, 2017]. Many researchers have reported the inhibition or delay of the effects of degenerative arthritis by inhibiting MMP-13 expression and suggest that the suppression of MMP-13 is very important for the mitigation of OA [Kim et al, 2011;Wang et al, 2013;Xie et al, 2017].…”

“…MMP-3 and MMP-13, in particular, are key players in the catabolic processes of OA, and they decompose aggrecan and COL2A1 which provide elasticity to the cartilage and aid shock relaxation [Wang et al, 2013;Xie et al, 2017]. Many researchers have reported the inhibition or delay of the effects of degenerative arthritis by inhibiting MMP-13 expression and suggest that the suppression of MMP-13 is very important for the mitigation of OA [Kim et al, 2011;Wang et al, 2013;Xie et al, 2017]. ADAMTS-4 is considered the primary enzyme responsible for the degradation of aggrecan during the pathogenesis of OA [Majumdar et al, 2007].…”