2-aminothiazole as a novel kinase inhibitor template.: Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor
2-aminothiazole as a novel kinase inhibitor template.: Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor
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DOI：
10.1021/jm060727j
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发表时间：
2006-11-16
影响因子：
7.3
通讯作者：
Barrish, Joel C.
中科院分区：
文献类型：
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作者：
Das, Jagabandhu;Chen, Ping;Barrish, Joel C.
通过筛选我们的内部化合物集合，发现 2-氨基噻唑 (1) 作为一种新型 Src 家族激酶抑制剂模板。通过连续结构-活性关系迭代的优化，确定了类似物 2（达沙替尼，BMS-354825）和 12m 作为泛 Src 抑制剂，在生化和细胞测定中具有纳摩尔至亚纳摩尔的效力。分子模型用于构建此类化合物抑制 Lck 的推定结合模型。该模型提出的关键氢键相互作用的框架与随后发表的与结构相似的 Abl 激酶结合的 2 的晶体结构一致。此类抑制剂的口服功效已通过 12m 在小鼠体内抑制促炎细胞因子 IL-2（ED50 与 5 mg/kg 相似）和降低急性炎症小鼠模型中的 TNF 水平（LPS 给药前 2 小时口服 60 mg/kg 时，LPS 诱导的 TNFR 产生抑制 90%）而得到证实。当每天两次口服 0.3 和 3 mg/kg 剂量时，12m 的口服功效在已患有疾病的大鼠的慢性佐剂关节炎模型中得到了进一步证明。达沙替尼 (Dasatinib) (2) 目前正在进行治疗慢性粒细胞白血病的临床试验。
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.