Propenyl Carboxamide Derivatives as Antagonists of Platelet Activating Factor

Article abstract of DOI:10.1021/jm00172a029

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-arylpentadienecarboxamides (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 -(1-butyl-6-methoxy-2-naphthyl)-N-<1-methyl-4-(3-pyridinyl)butyl>-2-propenamide (4b), -(3-butyl-6-methoxy-2-benzothiophene-yl)-N-<1-methyl-4-(3-pyridinyl)butyl>-2-propenamide (4k), and -(3-butyl-6-methoxy-1-methyl-2-indolyl)-N-<1-ethyl-4-(3-pyridinyl)butyl>-2-propenamide (4l) which inhibited PAF-induced bronchoconstriction 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.