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A series of N-[4-(3-pyridinyl)butyl]-1,1'-biphenyl-4-carboxamides was prepared, and the compounds were evaluated for platelet-activating factor (PAF) antagonist activity in a binding assay employing washed, whole dog platelets and in vivo for their ability to inhibit PAF-induced bronchoconstriction in the guinea pig. The inclusion of a methyl group in the R configuration on the side-chain carbon adjacent to the carboxamide nitrogen atom of these derivatives resulted in a marked enhancement of potency in the binding assay for compounds unsubstituted in the biphenyl 2-position and, more importantly, in improved oral bioavailability. Previous work with related pyrido[2,1-b]-quinazoline-8-carboxamides suggests that the presence of such an alkyl group improves bioavailability by rendering the resulting compounds resistant to degradation by liver amidases. The most interesting compounds to emerge from this work are (R)-2-bromo-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]-1,1'-bi phe nyl- 4-carboxamide (33) and (R)-2-butyl-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]- 1,1'-biphenyl-4-carboxamide (40) each of which inhibits PAF-induced bronchoconstriction in the guinea pig by greater than 55%. 6 h after an oral dose of 50 mg/kg.

A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,-E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxy-phenyl)-N- [1-methyl-4-(3-pyridinyl)butyl]- 2,4-pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4- (3-pyridinyl)butyl]-2,4-decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H- 1-(4-morpholinyl)-1-propanone (45).