Background:

TD-198946, a thienoindazole derivative, is a potent chondrogenic agent.

TD-198946 is a potent chondrogenic agent. TD-198946 strongly induces chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. TD-198946 induces stronger Col2a1 promoter activity than insulin in ATDC5 cells. In C3H10T1/2 cells, ATDC5 cells and primary mouse chondrocytes, TD-198946 dose-dependently stimulates endogenous expression of the chondrocyte markers Col2a1 and Acan, with maximum effects around 1-10 μM[1].

When administered directly into the joint space, TD-198946 successfully prevents and repaires degeneration of the articular cartilage. TD-198946 exerts its effect through the regulation of Runx1 expression, which is downregulated in both mouse and human OA cartilage compared with normal tissue[1]. TD-198946 has disease-modifying effects on progressed osteoarthritis. TD-198946 may prevent the progression of osteoarthritis by acting on the remaining chondrocytes rather than repairing damaged cartilage, it may be most effective as a therapeutic during the early or middle stages of osteoarthritis, before the articular cartilage is fully eroded[2]. Cartilaginous cell-sheets are generated by culturing mouse and canine costal chondrocytes and human mesenchymal stem cells with TD-198946 on temperature-responsive dishes. The transplanted cell-sheets are then successfully used to promote the reconstruction of permanent cartilage, with no evidence of chondrocyte hypertrophy in the knee articular cartilage defects created in mice and canines[3].

参考文献:
[1]. Yano F, et al. A novel disease-modifying osteoarthritis drug candidate targeting Runx1. Ann Rheum Dis. 2013 May;72(5):748-53.
[2]. Yano F, et al. Disease-modifying effects of TD-198946 on progressed osteoarthritis in a mouse model. Ann Rheum Dis. 2014 Nov;73(11):2062-4.
[3]. Yano F, et al. Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration. Biomaterials. 2013 Jul;34(22):5581-7.