title: Potent inhibitors of secretory phospholipase A2: synthesis and inhibitory activities of indolizine and indene derivatives.
abstract: Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.
authors.affiliation: Shiongi Research Laboratories, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hagishita
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Shirahase
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: Y
authors.initials: Y
authors.lastname: Murakami
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Matsuura
authors.forename: M
authors.initials: M
authors.lastname: Wada
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Ueno
authors.forename: Y
authors.initials: Y
authors.lastname: Chikazawa
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Ono
authors.forename: I
authors.initials: I
authors.lastname: Teshirogi
authors.forename: M
authors.initials: M
authors.lastname: Ohtani
mesh_terms: D000478:Alkylation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D007192:Indenes / Q000737:chemistry* / Q000494:pharmacology; D007212:Indolizines / Q000737:chemistry* / Q000494:pharmacology; D008745:Methylation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007192:Indenes; D007212:Indolizines; C035094:indolizine; C093581:indene; D010741:Phospholipases A; D054467:Phospholipases A2