| Abstract
| - 2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening ofour internal compound collection. Optimization through successive structure−activity relationship iterationsidentified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolarpotencies in biochemical and cellular assays. Molecular modeling was used to construct a putative bindingmodel for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactionsproposed by this model was in agreement with the subsequent, published crystal structure of 2 bound tostructurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m ininhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ∼ 5 mg/kg) and in reducing TNFlevels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production whendosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstratedin a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenousleukemia.
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