title: Propenyl carboxamide derivatives as antagonists of platelet activating factor.
abstract: A series of N-[4-(3-pyridinyl)butyl] 3-substituted propenyl carboxamide derivatives bearing an unsaturated bicyclic moiety in the 3-position was prepared and evaluated for PAF (platelet activating factor) antagonist activity. These compounds represent conformationally constrained direct analogues of the corresponding potent 5-aryl-pentadienecarboxamides (5). Most of the new compounds were active in a PAF-binding assay employing whole, washed dog platelets as the receptor source and inhibited PAF-induced bronchoconstriction in guinea pigs after intravenous administration. However, oral activity in the PAF-induced bronchoconstriction model was highly sensitive to the nature and substitution of the bicyclic ring system. The most interesting compounds included [R-(E)]-(1-butyl-6-methoxy-2-naphthyl)-N-[1-methyl-4-(3- pyridinyl)butyl]-2-propenamide (4b), [R-(E)]-(3-butyl-6-methoxy-2- benzo[b]thiophene-yl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2-propenamide (4k), and [R-(E)]-(3-butyl-6-methoxy-1-methyl-2-indoly)-N-[1-ethyl-4- (3-pyridinyl)butyl]-2-propenamide (4l) which inhibited PAF-induced broncho-constriction in guinea pigs with IC50s of 3.0-5.4 mg/kg, when the animals were challenged 2 h after drug treatment. They were also highly effective 6 h after a 50 mg/kg oral dose. This study supports the notion that the key remote aromatic ring present in the 5-arylpentadienecarboxamides (5) is preferentially coplanar with the diene system for good PAF antagonist activity.
authors.affiliation: Chemistry Research Department, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
authors.forename: R W
authors.initials: RW
authors.lastname: Guthrie
authors.forename: G L
authors.initials: GL
authors.lastname: Kaplan
authors.forename: F A
authors.initials: FA
authors.lastname: Mennona
authors.forename: J W
authors.initials: JW
authors.lastname: Tilley
authors.forename: R W
authors.initials: RW
authors.lastname: Kierstead
authors.forename: M
authors.initials: M
authors.lastname: O'Donnell
authors.forename: H
authors.initials: H
authors.lastname: Crowley
authors.forename: B
authors.initials: B
authors.lastname: Yaremko
authors.forename: A F
authors.initials: AF
authors.lastname: Welton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016085:Bronchoconstrictor Agents / Q000037:antagonists & inhibitors; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D016085:Bronchoconstrictor Agents; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor