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 Znchelating 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.
Keywords: Aggrecanase, ADAMTS-4, ADAMTS-5, inhibitors, structure-activity relationships
Current Medicinal Chemistry
Title: Progress Towards the Identification of New Aggrecanase Inhibitors
Volume: 16 Issue: 19
Author(s): Francesca De Rienzo, Puneet Saxena, Federico Filomia, Gianfranco Caselli, Fabrizio Colace, Luigi Stasi, Antonio Giordani and Maria Cristina Menziani
Affiliation:
Keywords: Aggrecanase, ADAMTS-4, ADAMTS-5, inhibitors, structure-activity relationships
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 Znchelating 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.
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De Rienzo Francesca, Saxena Puneet, Filomia Federico, Caselli Gianfranco, Colace Fabrizio, Stasi Luigi, Giordani Antonio and Menziani Cristina Maria, Progress Towards the Identification of New Aggrecanase Inhibitors, Current Medicinal Chemistry 2009; 16 (19) . https://dx.doi.org/10.2174/092986709788682092
DOI https://dx.doi.org/10.2174/092986709788682092 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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