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

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Abstract

Following the discovery of moderately potent antagonist activity platelet-activating factor (PAF) in 2-methyl-1-phenylimidazo[4,5-c]pyridine (2) (IC50 = 840 nM), 19 derivatives (3-21) were prepared which incorporated various lipophilic groups attached to the phenyl 4-position. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. [1,5]Benzodiazepines, e.g., 14 (2,3-dihydro-1-methyl-4-[4-(2-methylimidazo[4,5-c] pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-one) (IC50 = 4.9 nM, Ed50 = 0.03 mg/kg po), were found to possess equivalent or superior potency to the 1,4-dihydropyridine PAF antagonist UK-74,505 (1,4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2- [4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl) carbamoyl]pyridine) in vitro and in vivo. Furthermore, a potent benzazepine, 21 (7,8-dichloro-1-methyl-4-[4-(methylimidazo[4,5-c]pyrid-1-yl) phenyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one) (IC50 = 0.5 nM, ED50 = 0.03 mg/kg po), was discovered. These investigations prompted the synthesis 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.

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