Structural optimization of 4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines as antagonists for platelet activating factor : pharmacological contribution of substituents at the 2- and 6-positions of a condensed ring system

Summary A series of 4-(2-chlorophenyl)-9-methyl-6 H -thieno[3,2- f ][1,2,4]triazolo[4,3- a ][1,4]diazepine derivatives bearing substituents at the 2- and 6-positions were synthesized, and evaluated in vitro for their inhibitory activity on rabbit platelet aggregation induced by platelet activating factor (PAF) and in vivo for their preventing effect on PAF-induced mortality in mice. The length of alkyl or arylalkyl side chain at the 2-position was responsible for enhancing the affinity for the PAF receptor. The simultaneous substitution at both the 2- and 6-positions resulted in a successful separation of the affinity for the PAF receptor from that for the benzodiazepine (BZ) receptor. Thus, (±)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6 H -thieno[3,2- f ][1,2,4] triazolo[4,3- a ][1,4]diazepine (Y-24180) was confirmed to be a specific antagonist for the PAF receptor and is currently under clinical trials.