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

Osteoarthritis (OA) is a chronic and degenerative joint
disease
affecting more than 500 million patients worldwide with no disease-modifying
treatment approved to date. Several publications report on the transforming
growth factor β-activated kinase 1 (TAK1) as a potential molecular
target for OA, with complementary anti-catabolic and anti-inflammatory
effects. We report herein on the development of TAK1 inhibitors with
physicochemical properties suitable for intra-articular injection,
with the aim to achieve high drug concentration at the affected joint,
while avoiding severe toxicity associated with systemic inhibition.
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. Furthermore,
structure-based design allowed for an improvement of selectivity versus
interleukin-1 receptor-associated kinases 1 and 4 (IRAK1/4). Finally,
TAK-756 was discovered as a potent TAK1 inhibitor with good selectivity
versus IRAK1/4 as well as excellent intra-articular pharmacokinetic
properties.