N-Benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors
N-Benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors
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DOI：
10.1016/j.bmcl.2011.01.113
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发表时间：
2011-03-15
影响因子：
2.7
通讯作者：
Trilles, Richard
中科院分区：
文献类型：
--
作者：
Atkinson, Karen A.;Beretta, Elena E.;Trilles, Richard
确定了一种有效的小分子抑制剂，具有良好的药代动力学特征，允许在体内持续抑制SCD。从低分子量酰基胍(5a)开始，用RapidFire高通量质谱仪(RF-MS)鉴定，迭代文库设计被用来快速探测分子的酰胺和尾部区域。采用单态合成的方法研究核心区的变化。SCD抑制剂(5b)的生物学评价，包括SCD-1的体外效力和对低必需脂肪酸(Lefa)饮食大鼠血浆减饱和指数(DI)的体内调节。除了剂量依赖性的DI降低外，还注意到了对啮齿类动物眼组织的影响。因此，在大鼠中，这些SCD抑制剂仅概括了SCD-1基因敲除小鼠表现出的一部分表型。(C)2011爱思唯尔有限公司。保留所有权利。
A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse. (C) 2011 Elsevier Ltd. All rights reserved.