title: Design, synthesis, and biological evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic acids as new indole-based cytosolic phospholipase A2α inhibitors.
abstract: This article describes the design, synthesis, and biological evaluation of new indole-based cytosolic phospholipase A2α (cPLA2α, a group IVA phospholipase A2) inhibitors. A screening-hit compound from our library, (E)-3-{4-[(4-chlorophenyl)thio]-3-nitrophenyl}acrylic acid (5), was used to design a class of 3-(1-aryl-1H-indol-5-yl)propanoic acids as new small molecule inhibitors. The resultant structure-activity relationships studied using the isolated enzyme and by cell-based assays revealed that the 1-(p-O-substituted)phenyl, 3-phenylethyl, and 5-propanoic acid groups on the indole core are essential for good inhibitory activity against cPLA2α. Optimization of the p-substituents on the N1 phenyl group led to the discovery of 56n (ASB14780), which was shown to be a potent inhibitor of cPLA2α via enzyme assay, cell-based assay, and guinea pig and human whole-blood assays. It displayed oral efficacy toward mice tetradecanoyl phorbol acetate-induced ear edema and guinea pig ovalbumin-induced asthma models.
authors.affiliation: Faculty of Pharmaceutical Chemistry, ‡R&D Administration, §Exploratory Technology, ∥Drug Discovery Technology, and ⊥Pharmacology I, Asubio Pharma Co., Ltd. , 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tomoo
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakatsuka
authors.forename: Toyoko
authors.initials: T
authors.lastname: Katayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujieda
authors.forename: Maki
authors.initials: M
authors.lastname: Terakawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagahira
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001249:Asthma / Q000139:chemically induced / Q000517:prevention & control; D003600:Cytosol / Q000201:enzymology; D004285:Dogs; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D015394:Molecular Structure; D010047:Ovalbumin; D011422:Propionates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate; D020298:U937 Cells
chemical_list: C000593222:3-(1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl)propanoic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D011422:Propionates; C030374:indole; D010047:Ovalbumin; D054513:Group IV Phospholipases A2; C029658:propionic acid; D013755:Tetradecanoylphorbol Acetate