title: Design and synthesis of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones as inhibitors of human cytosolic phospholipase A2alpha.
abstract: A series of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones was synthesized and assessed for the ability to inhibit cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Several of these compounds were found to be active in both a cell based assay and an isolated enzyme assay. The most potent inhibitor was the thiazolidine-2,4-dione substituted derivative 35. With IC(50)-values of 0.7 muM and 7.3 muM in the cellular and isolated enzyme assay, respectively, it possesses similar inhibitory potency as the known cPLA(2)alpha inhibitor arachidonyltrifluoromethyl ketone (AACOCF(3)). Structure-activity relationship studies revealed that the evaluated isobenzofuran-1-ones seem to exert their cellular activities not only by a direct interaction with the enzyme but also by other as yet unknown mechanisms.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Hess
authors.forename: Alwine
authors.initials: A
authors.lastname: Schulze Elfringhoff
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D011758:Pyrroles; D054513:Group IV Phospholipases A2; C105430:benzofuran