Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue 23, Pages 6819-6832Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm060727j
Keywords
-
Categories
Ask authors/readers for more resources
2-Aminothiazole ( 1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 ( Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice ( ED50 similar to 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation ( 90% inhibition in LPS-induced TNFR production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib ( 2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available