title: Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2.
abstract: We report a series of inhibitors of secreted phospholipases A2 (sPLA2s) based on substituted indoles, 6,7-benzoindoles, and indolizines derived from LY315920, a well-known indole-based sPLA2 inhibitor. Using the human group X sPLA2 crystal structure, we prepared a highly potent and selective indole-based inhibitor of this enzyme. Also, we report human and mouse group IIA and IIE specific inhibitors and a substituted 6,7-benzoindole that inhibits nearly all human and mouse sPLA2s in the low nanomolar range.
authors.affiliation: Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Rob C
authors.initials: RC
authors.lastname: Oslund
authors.forename: Nathan
authors.initials: N
authors.lastname: Cermak
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D054836:Indolizidines / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D054836:Indolizidines; D054497:Phospholipases A2, Secretory