title: Design and synthesis of 1-indol-1-yl-propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha.
abstract: The synthesis and structure-activity relationship study of a series of 1-indol-1-yl-3-phenoxypropan-2-one inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) are described. The compounds were evaluated in a vesicle assay with isolated cPLA(2)alpha and in cellular assays with intact human platelets. Systematic variation led to 3-methylhydrogen 1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-3,5-dicarboxylate (57), which revealed the highest activity against the isolated enzyme. With an IC(50) value of 4.3 nM in this assay, it is one of the most potent in vitro cPLA(2)alpha inhibitors known today.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Ludwig
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bovens
authors.forename: Carsten
authors.initials: C
authors.lastname: Brauch
authors.forename: Alwine Schulze
authors.initials: AS
authors.lastname: Elfringhoff
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054513:Group IV Phospholipases A2; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D011407:Propane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007659:Ketones; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D011407:Propane