用于酶抑制剂设计的基本α-酮杂环取代基效应的描述。
Delineation of a fundamental alpha-ketoheterocycle substituent effect for use in the design of enzyme inhibitors.
作者信息
Romero F Anthony, Hwang Inkyu, Boger Dale L
机构信息
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
出版信息
J Am Chem Soc. 2006 Nov 1;128(43):14004-5. doi: 10.1021/ja064522b.
Abstract
The synthesis and examination of a systematic series of 5-substituted 2-keto oxazoles as inhibitors of fatty acid amide hydrolase (FAAH) defined a fundamental substituent effect that led to the discovery of inhibitors with Ki's as low as 400 pM. The intrinsic basis of the relationship (-log Ki vs sigmap), which relates Ki with the Hammett sigmap constant of the substituent, the magnitude of the effect (rho = 3.01), and its predictive value (R2 = 0.91) suggest a widespread applicability in studies beyond FAAH.
摘要
合成并检测了一系列作为脂肪酸酰胺水解酶（FAAH）抑制剂的5-取代-2-酮恶唑，确定了一种基本的取代基效应，从而发现了Ki低至400 pM的抑制剂。这种关系（-log Ki对sigmap）的内在基础，即将Ki与取代基的哈米特sigmap常数相关联，效应大小（rho = 3.01）及其预测值（R2 = 0.91）表明其在FAAH以外的研究中具有广泛的适用性。
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2
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3
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4
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J Pharmacol Exp Ther. 2004 Nov;311(2):441-8. doi: 10.1124/jpet.104.069401. Epub 2004 Jun 30.
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Curr Opin Chem Biol. 2003 Aug;7(4):469-75. doi: 10.1016/s1367-5931(03)00079-6.
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