Identification\nof TAK-756, A Potent TAK1 Inhibitor\nfor the Treatment of Osteoarthritis through Intra-Articular Administration

Osteoarthritis (OA) is a chronic and degenerative joint\ndisease\naffecting more than 500 million patients worldwide with no disease-modifying\ntreatment approved to date. Several publications report on the transforming\ngrowth factor β-activated kinase 1 (TAK1) as a potential molecular\ntarget for OA, with complementary anti-catabolic and anti-inflammatory\neffects. We report herein on the development of TAK1 inhibitors with\nphysicochemical properties suitable for intra-articular injection,\nwith the aim to achieve high drug concentration at the affected joint,\nwhile avoiding severe toxicity associated with systemic inhibition.\nMore specifically, reducing solubility by increasing crystallinity,\nwhile maintaining moderate lipophilicity proved to be a good compromise\nto ensure high and sustained free drug exposures in the joint. Furthermore,\nstructure-based design allowed for an improvement of selectivity versus\ninterleukin-1 receptor-associated kinases 1 and 4 (IRAK1/4). Finally,\nTAK-756 was discovered as a potent TAK1 inhibitor with good selectivity\nversus IRAK1/4 as well as excellent intra-articular pharmacokinetic\nproperties.