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1-（5-羧基吲唑-1-基）丙烷-2-酮作为胞质磷脂酶Aα和脂肪酸酰胺水解酶的双重抑制剂：羧酸部分的生物电子等排体替代

1-(5-Carboxyindazol-1-yl)propan-2-ones as dual inhibitors of cytosolic phospholipase Aα and fatty acid amide hydrolase: bioisosteric replacement of the carboxylic acid moiety.

作者信息

Althaus Jan, Hake Theresa, Hanekamp Walburga, Lehr Matthias

机构信息

a Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Germany.

出版信息

J Enzyme Inhib Med Chem. 2016;31(sup1):131-140. doi: 10.1080/14756366.2016.1178246. Epub 2016 May 9.

DOI:10.1080/14756366.2016.1178246
PMID:27162011
Abstract

Indazole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent dual inhibitors of cytosolic phospholipase Aα (cPLAα) and fatty acid amide hydrolase (FAAH). In continuation of our structure-activity studies on cPLAα and FAAH inhibitors, a number of derivatives of these substances characterized by bioisosteric replacement of the carboxylic acid functionality by inverse amides, sulfonylamides, carbamates and ureas were prepared. The biological evaluation of the obtained compounds showed that the carboxylic acid functionality of the lead compounds is of special importance for a pronounced inhibition of cPLAα and FAAH.

摘要

先前有报道称，在1位带有3-芳氧基-2-氧代丙基残基的吲唑-5-羧酸是胞质磷脂酶Aα（cPLAα）和脂肪酸酰胺水解酶（FAAH）的有效双重抑制剂。在我们对cPLAα和FAAH抑制剂的构效关系研究中，我们制备了这些物质的许多衍生物，其特征是通过反向酰胺、磺酰胺、氨基甲酸酯和脲对羧酸官能团进行生物电子等排体置换。对所得化合物的生物学评价表明，先导化合物的羧酸官能团对于显著抑制cPLAα和FAAH特别重要。

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