Biphenylcarboxamide derivatives as antagonists of platelet-activating factor.
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.
Chemistry Research Department, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110.
J W
JW
Tilley
J W
JW
Clader
S
S
Zawoiski
M
M
Wirkus
R A
RA
LeMahieu
M
M
O'Donnell
H
H
Crowley
A F
AF
Welton
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001986:Bronchial Spasm / Q000188:drug therapy; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006168:Guinea Pigs; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D010972:Platelet Activating Factor