A study from Xiaojing Wang discovered and identified a novel Btk inhibitor G-744 that has potential to treat arthritis.

Bruton’s tyrosine kinase (Btk) plays an indispensable role in the function of B cells and myeloid cells. Therefore, Btk has become an attractive target for immunological disorders treatment, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and B-cell lymphomas. It’s encouraging that some Btk inhibitors have been marketed. Ibrutinib, a Btk inhibitor, has been recently approved for treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia.

In the study, the authors verified G-744 as a highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.

Besides, in vitro, G-744 is a Btk inhibitor with an IC₅₀ of 2 nM.

In pharmacokinetic experiments, G-744 exhibited low to moderate clearance in four preclinical species. And G-744 showed excellent oral activity in animal models.

In addition, in female Lewis rat based CIA models, the authors treated rats with G-744 by oral administration daily, with doses of 6.25, 12.25, 25 mg/kg. As a result, all three doses resulted in a significant dose-dependent inhibition of ankle thickness between day 10 and day 17 (onset of increase in ankle diameter on day 9). In other words, G-744 (6.25/12.25/25 mg/kg, p.o., b.i.d., daily) protected Lewis rats from collagen-induced arthritis dose-dependently.

But until now, in vitro experiments are still lacked. G-744 need to be verified further and further.

Reference:
Wang X, et al. Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties. ACS Med Chem Lett. 2017 May 3;8(6):608-613.