title: 1-(5-Carboxyindazol-1-yl)propan-2-ones as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase: bioisosteric replacement of the carboxylic acid moiety.
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 A2α (cPLA2α) and fatty acid amide hydrolase (FAAH). In continuation of our structure-activity studies on cPLA2α 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 cPLA2α and FAAH.
authors.affiliation: a Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Althaus
authors.affiliation: a Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Hake
authors.affiliation: a Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Germany.
authors.forename: Walburga
authors.initials: W
authors.lastname: Hanekamp
authors.affiliation: a Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002264:Carboxylic Acids; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011407:Propane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D054513:Group IV Phospholipases A2; D007191:Indazoles; D011407:Propane; D000099252:Fatty Acid Amide Hydrolases; C000614298:1-(5-carboxyindazol-1-yl)propan-2-one
keywords: Bioisosteric replacement; cytosolic phospholipase A2α; fatty acid amide hydrolase; indazol-1-ylpropan-2-ones; inhibitor