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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.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2006 Nov 16 , DOI: 10.1021/jm060727j
Jagabandhu Das 1 , Ping Chen 1 , Derek Norris 1 , Ramesh Padmanabha 1 , James Lin 1 , Robert V. Moquin 1 , Zhongqi Shen 1 , Lynda S. Cook 1 , Arthur M. Doweyko 1 , Sidney Pitt 1 , Suhong Pang 1 , Ding Ren Shen 1 , Qiong Fang 1 , Henry F. de Fex 1 , Kim W. McIntyre 1 , David J. Shuster 1 , Kathleen M. Gillooly 1 , Kamelia Behnia 1 , Gary L. Schieven 1 , John Wityak 1 , Joel C. Barrish 1
Affiliation  

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 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha 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.

中文翻译:

2-氨基噻唑作为新型激酶抑制剂模板。结构活性关系研究对发现N-(2-氯-6-甲基苯基)-2-[[[6- [4-(2-羟乙基)-1-哌嗪基)]-2-甲基-4-嘧啶基的发现氨基]]-1,3-噻唑-5-羧酰胺(dasatinib,BMS-354825)作为有效的pan-Src激酶抑制剂。

通过筛选我们的内部化合物集合,发现了2-氨基噻唑(1)作为一种新型Src家族激酶抑制剂模板。通过连续的结构-活性关系迭代进行的优化确定了类似物2(Dasatinib,BMS-354825)和12m是在生化和细胞分析中具有纳摩尔至亚纳摩尔浓度的pan-Src抑制剂。分子模型被用来构建推定的结合模型,以抑制这类化合物对Lck的抑制作用。该模型提出的关键氢键相互作用的框架与随后公布的与结构相似的Abl激酶结合的2的晶体结构一致。此类抑制剂的口服药效为12m,可在小鼠体内体外抑制促炎细胞因子IL-2(ED50约为5 mg / kg),并在急性小鼠炎症模型中降低TNF水平(LPS抑制90%) LPS给药前2小时以60 mg / kg口服给药时,TNF-α诱导的TNFα产生)。当每天两次以0.3和3 mg / kg口服给药时,在已确诊疾病的大鼠的慢性佐剂性关节炎模型中进一步证明了12m的口服功效。达沙替尼(2)目前正在临床试验中,用于治疗慢性粒细胞性白血病。当每天两次以0.3和3 mg / kg口服给药时,在已确诊疾病的大鼠的慢性佐剂性关节炎模型中进一步证明了12m的口服功效。达沙替尼(2)目前正在临床试验中,用于治疗慢性粒细胞性白血病。当每天两次以0.3和3 mg / kg口服给药时,在已确诊疾病的大鼠的慢性佐剂性关节炎模型中进一步证明了12m的口服功效。达沙替尼(2)目前正在临床试验中,用于治疗慢性粒细胞性白血病。
更新日期:2017-01-31
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