Our efforts to prepare inhibitors of JAK family kinases with a selective JAK1/3 profile led to the discovery of a series of pyrrolo[1,2-b]pyridazine-3-carboxamides. An early lead compound caused profound hemodynamic effects, which were believed to be a result of poor selectivity against a number of kinases, including those in the ROCK family. Compounds with improved selectivity were designed based on structural differences between JAK3 and ROCK. This led to the identification of a compound which produced minimal heart rate and blood pressure changes in a mouse telemetry study.

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as potent JAK1/3 inhibitors with selectivity against ROCK family kinases

255th National Meeting (2018)

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