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 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.
Fray
M J
MJ
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, UK.
Cooper
K
K
Parry
M J
MJ
Richardson
K
K
Steele
J
J
D000818:Animals; D001381:Azepines / Q000737:chemistry; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry
C095432:2-methyl-1-phenylimidazo(4,5-c)pyridine; D001381:Azepines; D007093:Imidazoles; D010972:Platelet Activating Factor; D011725:Pyridines; D013844:Thiazoles; D014230:Triazoles; D001569:Benzodiazepines; C053706:N-(3-chlorophenyl)-3-(3-pyridinyl)-1H,3H-pyrrolo(1,2-c)thiazole-7-carboxamide; C063964:bepafant