The design, synthesis, and SAR for a series of aminothiazole pyrimidines as potent LIMK1 and LIMK2 inhibitors are described. Appropriate choice of substituents led to molecules with good selectivity for either enzyme. An advanced member (compound 31)  of the series was shown to effectively interfere with the phosphorylation of the LIM kinases substrate cofilin. Consistent with the important role of the LIM kinases in regulating cytoskeletal structure, treated cells displayed dramatically reduced F-actin content.

Modulation of cofilin phosphorylation by inhibition of the Lim family kinases

244th National Meeting (2012)

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