NOVEL ANTAGONISTS OF PLATELET-ACTIVATING-FACTOR .1. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF BENZODIAZEPINE AND BENZAZEPINE DERIVATIVES OF 2-METHYL-1-PHENYLIMIDAZO[4,5-C]PYRIDINE

Following the discovery of moderately potent antagonist activity again st platelet-activating factor (PAF) in 2-methyl-1-phenylimidazo[4,5-c] pyridine (2) (IC50 = 840 nM), 19 derivatives (3-21) were prepared whic h incorporated various lipophilic groups attached to the phenyl 4-posi tion. Structure-activity relationships were evaluated where PAF antago nist activity was measured in vitro by determining the concentration o f compound (IC50) required to inhibit the PAF-induced aggregation of r abbit washed platelets and in vivo by determining the oral dose (ED(50 )) which protected mice from a lethal injection of PAF. [1,5]Benzodiaz epines, e.g., 14 -c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-one) (I C50 = 4.9 nM, ED(50) = 0.03 mg/kg po), were found to possess equivalen t or superior potency to the 1,4-dihydropyridine PAF antagonist UK-74, 505 (1, idazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl)car bamoyl]pyri dine) in vitro and in vivo. Furthermore, a potent benzazepine, 21 )phe nyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one) (IC50 = 0.5 nM, ED(50) = 0.03 mg/kg po), was discovered. These investigations prompted the sy nthesis and evaluation of additional diazepine derivatives, which are described in the following paper. The relationship between the key PAF antagonist pharmacophores of 2-methyl-1-phenylimidazo[4,5-c]pyridine, a triazolothienodiazepine (WEB2170), and a pyrrolothiazolidine (RP-52 ,770) is discussed.