title: Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors.
abstract: A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.
authors.affiliation: Immunoscience Research, Abbott Laboratories, D47K, AP10, 100 Abbott Park Road, Abbott Park, Illinois 600064, USA. teodozyj.kolasa@abbott.com
authors.forename: T
authors.initials: T
authors.lastname: Kolasa
authors.forename: D E
authors.initials: DE
authors.lastname: Gunn
authors.forename: P
authors.initials: P
authors.lastname: Bhatia
authors.forename: K W
authors.initials: KW
authors.lastname: Woods
authors.forename: T
authors.initials: T
authors.lastname: Gane
authors.forename: A O
authors.initials: AO
authors.lastname: Stewart
authors.forename: J B
authors.initials: JB
authors.lastname: Bouska
authors.forename: R R
authors.initials: RR
authors.lastname: Harris
authors.forename: K I
authors.initials: KI
authors.lastname: Hulkower
authors.forename: P E
authors.initials: PE
authors.lastname: Malo
authors.forename: R L
authors.initials: RL
authors.lastname: Bell
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
authors.forename: C D
authors.initials: CD
authors.lastname: Brooks
mesh_terms: D000180:Acrylic Resins; D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001202:Ascitic Fluid / Q000378:metabolism; D006099:Granuloma / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011001:Pleuropneumonia / Q000188:drug therapy; D011014:Pneumonia / Q000188:drug therapy; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007975:Leukotriene B4; D011804:Quinolines; D000099166:Polyacrylamides; C112380:A 93176