title: Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.
abstract: Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Dillard
authors.forename: N J
authors.initials: NJ
authors.lastname: Bach
authors.forename: S E
authors.initials: SE
authors.lastname: Draheim
authors.forename: D R
authors.initials: DR
authors.lastname: Berry
authors.forename: D G
authors.initials: DG
authors.lastname: Carlson
authors.forename: N Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: D K
authors.initials: DK
authors.lastname: Clawson
authors.forename: L W
authors.initials: LW
authors.lastname: Hartley
authors.forename: L M
authors.initials: LM
authors.lastname: Johnson
authors.forename: N D
authors.initials: ND
authors.lastname: Jones
authors.forename: E R
authors.initials: ER
authors.lastname: McKinney
authors.forename: E D
authors.initials: ED
authors.lastname: Mihelich
authors.forename: J L
authors.initials: JL
authors.lastname: Olkowski
authors.forename: R W
authors.initials: RW
authors.lastname: Schevitz
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: D W
authors.initials: DW
authors.lastname: Snyder
authors.forename: C D
authors.initials: CD
authors.lastname: Sommers
authors.forename: J P
authors.initials: JP
authors.lastname: Wery
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007210:Indoleacetic Acids / Q000737:chemistry / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; C015950:indoleacetamide; D010741:Phospholipases A; D054467:Phospholipases A2