1-Heteroarylpropan-2-ones as inhibitors of fatty acid amide hydrolase: Studies on structure-activity relationships and metabolic stability

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• 作者：Stefan Zahov ; David Garzinsky ; Walburga Hanekamp ; Matthias Lehr ; ^{lehrm@uni-muenster.de}
• 关键词：Propan-2-one ; Fatty acid amide hydrolase ; Enzyme inhibition ; Metabolic stability ; Aqueous solubility
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：825-837
• 全文大小：1601 K
• 卷排序：25

文摘

The serine hydrolase fatty acid amide hydrolase (FAAH) catalyzes the degradation of the endocannabinoid anandamide, which possesses analgesic and anti-inflammatory effects. A new series of 1-heteroarylpropan-2-ones was synthesized and evaluated for FAAH inhibition. Structure-activity relationship studies revealed that 1H-benzotriazol-1-yl, 1H-7-azabenzotriazol-1-yl, 1H-tetrazol-1-yl and 2H-tetrazol-2-yl substituents have the highest impact on inhibitory potency. Furthermore, attempts were made to increase the limited metabolic stability of the ketone functionality of these compounds towards metabolic reduction by introduction of shielding alkyl substituents in proximity of this serine reactive group.