This poster will describe a series of pyrrolopyridazine based JAK inhibitors and discuss the modifications made to the 4-position of the chemotype in order to achieve the requisite levels of kinase selectivity. Originating from a lead class of compounds (I), observed improvements in JAK family selectivity for an extended class of molecules (II) will be rationalized by molecular modelling. Application of this same extension approach will be applied to a sub-optimal series of reverse amides (III) with an oxazole motif serving as both an amide isostere and the extension group leading to molecules of the type (IV). Finally, the poster will highlight efforts to improve the physicochemical properties of this series and will describe both the in-vitro and in-vivo profile of compound (V).

Achieving desired levels of selectivity for a series of “acyclic-based” JAK inhibitors

249th National Meeting (2015)

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