Tofacitinib (1), a JAK family kinase inhibitor has been approved in the United States for rheumatoid arthritis (RA). However a lack of JAK family selectivity is believed to result in dose limiting side effects. As part of our efforts to identify an improved profile, we prepared compound 2, which was a functionally selective JAK1/3 inhibitor, however progression to in vivo efficacy models was prevented by dose limiting solubility. Identification of a suitable phosphate pro-drug (3) enabled advancement to a murine collagen induced arthritis model. High levels of efficacy were observed at doses which showed no effect on hematopoiesis. These results suggest a JAK1/3 inhibitor profile may have utility in the treatment of rheumatoid arthritis and other autoimmune diseases.

Discovery of 4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (BMT-1438), a potent JAK1/3 inhibitor and the use of a phosphate prodrug in demonstrating efficacy in a rheumatoid arthritis model

253rd National Meeting (2017)

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