Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2
Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2
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DOI：
10.1016/j.bmcl.2009.04.091
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发表时间：
2010-04-01
影响因子：
2.7
通讯作者：
Esler, William
中科院分区：
文献类型：
--
作者：
Corbett, Jeffrey W.;Freeman-Cook, Kevin D.;Esler, William
通过对辉瑞化合物文库的筛选，鉴定出弱的乙酰辅酶A羧基酶抑制剂，得到了rACC1CT结构域共晶结构。利用HTS HITS和基于结构的药物发现，设计了一种更刚性的抑制剂，并导致发现了亚微摩尔、螺满酮非特异性ACC抑制剂。从这种化学类型中获得了表现出良好的大鼠药代动力学的低纳摩尔、非特异性ACC同工酶抑制剂。(C)2010爱思唯尔有限公司。保留所有权利。
Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype. (C) 2010 Elsevier Ltd. All rights reserved.