Progress Towards the Identification of New Aggrecanase Inhibitors

Abstract

Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.

Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis

“…Since the discovery of its importance in OA onset and progression, ADAMTS5 has been pursued as a target for therapies aimed at disease modification, with strategies employing design of small molecules to inhibit its protease activity 3,14 . Unfortunately this search has been rewarded with little success, likely because of the high homology of the catalytic domain across the diverse metalloprotease families, and the resulting difficulties at achieving specificity in order to avoid a burden of undesired effects.…”

The anti-catabolic role of bovine lactoferricin in cartilage

“…In particular, in human articular chondrocytes and synovial fibroblasts treated with IL-1β and FGF-2, the expression of matrixdegrading enzymes (i.e., MMP-1, MMP-3, and MMP-13) and ADAMTSs (i.e., ADAMTS4 and ADAMTS5) were downregulated at both the mRNA and protein levels in the presence of LfcinB. This finding is significant, as MMPs and ADAMTSs have been shown to contribute to cartilage degradation (22), and finding ways to decrease their activities has been the focus of multiple studies (23,24).…”

Advances in the development of novel aggrecanase inhibitors

“…Wyeth's interest in this series is further highlighted by two additional applications covering chemical processes for synthesis [17,18] and another application covering polymorphs of compound 5 [19]. Later in 2007, a Wyeth patent application covering a series of thiadiazole-based inhibitors (8) was published [20]. Most of the compounds exemplified in this application have modest potency (> 1 µM) at ADAMTS-5.…”

“…The most recent review of the published scientific literature was published in 2009 [8]. This review is organized by company which allows for a focus around a particular scaffold or series of scaffolds.…”