Development of a selective matrix metalloproteinase 13 (MMP-13) inhibitor for the treatment of Osteoarthritis

Osteoarthritis (OA) is a chronic disorder that causes damage to the cartilage and surrounding tissues and is characterized by pain, stiffness, and loss of function. Current treatments for OA primarily involve providing only relief of symptoms but does not affect the overall trajectory of the disease. A major goal for treating OA has been to slow down or reverse disease progression. Matrix metalloproteinase-13 (MMP-13) is expressed by chondrocytes and synovial cells in human OA and is thought to play a critical role in cartilage destruction. Herein we report a new, allosteric MMP-13 inhibitor, AQU-019, that has been optimized for potency, metabolic stability, and oral bioavailability through a combination of structure activity relationship (SAR) and deuterium substitution as a potential disease modifying OA drug (DMOAD). The inhibitor was demonstrated to be chondroprotective when injected intraarticular (IA) in the monoiodoacetic acid (MIA) rat model of OA.