Wang Xueqing, Sarris Katerina, Kage Karen, Zhang Di, Brown Scott P, Kolasa Teodozyi, Surowy Carol, El Kouhen Odile F, Muchmore Steven W, Brioni Jorge D, Stewart Andrew O
Neuroscience Research, Global Pharmaceutical Research and Development, AP10/303, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Med Chem. 2009 Jan 8;52(1):170-80. doi: 10.1021/jm801042a.
High-throughput screening (HTS) identified benzothiazole analogue 3 as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compounds may provide useful tools for the study of FAAH and the endocannabinoid system.
高通量筛选（HTS）确定苯并噻唑类似物3为一种有效的脂肪酸酰胺水解酶（FAAH）抑制剂。构效关系（SAR）研究表明，磺酰基、哌啶环和苯并噻唑是其活性的关键组成部分，16j是该系列中最有效的类似物。化合物3的时间依赖性预孵育研究表明它是一种可逆抑制剂。对大鼠组织中3进行的基于活性的蛋白质谱分析（ABPP）评估显示，它具有出色的选择性，对其他丝氨酸水解酶没有脱靶活性。3与一种已知的FAAH抑制剂的分子形状叠加表明，这些化合物可能作为过渡态类似物，与催化残基形成推定的氢键并模拟四面体过渡态的电荷分布。建模研究还表明，苯并噻唑环与酶的疏水相互作用有助于其非凡的效力。这些化合物可能为FAAH和内源性大麻素系统的研究提供有用的工具。
