title: Structure-activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps.
abstract: Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are serine hydrolases. cPLA2α is involved in the generation of pro-inflammatory lipid mediators, FAAH terminates the anti-inflammatory effects of endocannabinoids. Therefore, inhibitors of these enzymes may represent new drug candidates for the treatment of inflammation. We have reported that certain 1-heteroarylpropan-2-ones are potent inhibitors of cPLA2α and FAAH. The serine reactive ketone group of these compounds, which is crucial for enzyme inhibition, is readily metabolized resulting in inactive alcohol derivatives. In order to obtain metabolically more stable inhibitors, we replaced this moiety by α-ketoheterocyle, cyanamide and nitrile serine traps. Investigations on activity and metabolic stability of these substances revealed that in all cases an increased metabolic stability was accompanied by a loss of inhibitory potency against cPLA2α and FAAH, respectively.
authors.affiliation: a Department of Chemistry and Pharmacy , Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Münster , Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Sundermann
authors.affiliation: a Department of Chemistry and Pharmacy , Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Münster , Germany.
authors.forename: Walburga
authors.initials: W
authors.lastname: Hanekamp
authors.affiliation: a Department of Chemistry and Pharmacy , Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Münster , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; 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; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011407:Propane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012694:Serine / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D054513:Group IV Phospholipases A2; D007659:Ketones; D011407:Propane; D012694:Serine; D000099252:Fatty Acid Amide Hydrolases; C516389:PLA2G4A protein, human
keywords: Cytosolic phospholipase A2α; fatty acid amide hydrolase; inhibitor; metabolic stability; serine trap