Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.
Lucas MC, Bhagirath N, Chiao E, Goldstein DM, Hermann JC, Hsu PY, Kirchner S, Kennedy-Smith JJ, Kuglstatter A, Lukacs C, Menke J, Niu L, Padilla F, Peng Y, Polonchuk L, Railkar A, Slade M, Soth M, Xu D, Yadava P, Yee C, Zhou M, Liao C.
Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.