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Structure–Activity Relationships of α-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase

机译:脂肪酸酰胺水解酶α-酮基恶唑抑制剂的构效关系

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摘要

A systematic study of the structure–activity relationships (SAR) of >2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., >5c, aryl = 1-napthyl, Ki = 2.6 nM) with >5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than >2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which >11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (>12p, 6-position S, Ki = 3 nM or >13d, 2-position OH, Ki = 8 nM) comparable in potency to >2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
机译:针对强酰胺脂肪酸酰胺水解酶(FAAH)的> 2b (OL-135)的构效关系(SAR)进行了系统研究,详细针对C2酰基侧链。末端苯基的一系列芳基取代基或取代基提供了> 5hh 的有效抑制剂(例如,> 5c ,芳基= 1-萘基,Ki = 2.6 nM)(芳基= 3-Cl-Ph,Ki = 900 pM)比> 2b 强5倍。检查了构象受限的C2侧链,并提供了许多非常有效的抑制剂,其中> 11j (乙基联苯侧链)被确定为750 pM抑制剂。研究了系统性的一系列杂原子(O,NMe,S),吸电子基团(SO,SO2)和位于连接侧链内的酰胺以及羟基取代基上的酰胺,这些取代基通常导致效能下降。耐受性最高的位置提供的有效抑制剂(> 12p ,6位S,Ki = 3 nM或> 13d ,2位OH,Ki = 8 nM)的效价与> 2b 。从系统的100多个候选候选蛋白中对所选抑制剂进行蛋白质组学筛选,发现与其他所有哺乳动物丝氨酸蛋白酶相比,FAAH具有选择性。

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