Langlois, Jean-Baptiste (2024) Identification of TAK-756, a potent and selective TAK1 inhibitor for the treatment of osteoarthritis through intra-articular administration. Journal of medicinal chemistry.

Abstract

Osteoarthritis (OA) is a chronic and degenerative joint disease affecting more than 500 million patients worldwide. It is characterized by cartilage degeneration along with low grade synovial inflammation. The onset of OA is multifactorial (e.g. ageing, trauma, obesity and/or genetic) but typically converges towards a progressive diminution of patient’s mobility, and eventually, a deterioration in health. The societal burden of OA is not easily quantifiable but is compounded by the fact that no disease-modifying treatments have been approved to date. Patients are prescribed management therapies (e.g. physical activity programs, viscosupplementation and/or pain killers) until surgical interventions become inevitable (last resort option being a total knee replacement procedure). In this context, several publications report on the transforming growth factor -activated kinase 1 (TAK1) as a potential molecular target for inflammatory arthritides, with complementary anti-catabolic and anti-inflammatory effects. However, severe toxicity has been reported for various TAK1 transgenic mice models, constituting an important hurdle in the development of a chronic treatment for OA. We report herein on the development of TAK1 inhibitors with physicochemical properties suitable for intra-articular injection. Indeed, the injection of a local depot often leads to high drug concentration in the targeted joint, while maintaining low systemic exposure, hence improving the overall safety profile. The desired drug candidate would have to provide long-lasting exposure in the knee joint to reduce the number of intra-articular injections and increase patient compliance. Optimization towards this target product profile placed us in an unusual property space and notably required us to optimize for insolubility in simulated biofluids. More specifically, reducing solubility by increasing crystallinity, while maintaining moderate lipophilicity proved to be a good compromise to ensure high and sustained free drug exposures in the joint. Finally, TAK-756 was discovered as a potent and selective TAK1 inhibitor with excellent intra-articular pharmacokinetic properties.

Item Type:	Article
Date Deposited:	10 Dec 2024 00:45
Last Modified:	10 Dec 2024 00:45
URI:	https://oak.novartis.com/id/eprint/54603