Otrubova Katerina, Boger Dale L
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
ACS Chem Neurosci. 2012 May 16;3(5):340-348. doi: 10.1021/cn2001206. Epub 2011 Dec 20.
A summary of the initial discovery and characterization of the enzyme fatty acid amide hydrolase (FAAH), and the subsequent advancement of an important class of competitive, reversible, potent and selective inhibitors is presented. Initially explored using substrate-inspired inhibitors bearing electrophilic carbonyls, the examination of α-ketoheterocyle-based inhibitors of FAAH with the benefit of a unique activity-based protein-profiling (ABPP)-based proteome-wide selectivity assay, a powerful in vivo biomarker-based in vivo screen, and subsequent retrospective X-ray co-crystal structures with the enzyme, is summarized. These efforts defined the impact of the central activating heterocycle and its key substituents, provided key simplifications in the C2 acyl side chain and clear interpretations for the unique role and subsequent optimization of the central activating heterocycle, and established the basis for the recent further conformational constraints in the C2 acyl side chain, providing potent, long-acting, orally-active FAAH inhibitors.
本文介绍了脂肪酸酰胺水解酶（FAAH）的初步发现和特性总结，以及一类重要的竞争性、可逆性、强效和选择性抑制剂的后续进展。最初使用带有亲电羰基的底物启发型抑制剂进行探索，总结了基于独特的基于活性的蛋白质谱分析（ABPP）的全蛋白质组选择性测定、强大的基于体内生物标志物的体内筛选以及随后与该酶的回顾性X射线共晶体结构，对基于α-酮杂环的FAAH抑制剂的研究。这些工作确定了中心活化杂环及其关键取代基的影响，简化了C2酰基侧链，明确了解释了中心活化杂环的独特作用及后续优化，并为最近在C2酰基侧链中进一步的构象限制奠定了基础，从而提供了强效、长效、口服活性的FAAH抑制剂。
