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

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.

Platelet-Activating Factor Antagonists Decrease Follicular Dendritic-Cell Stimulation of Human B Lymphocytes

“…This allowed direct observation of the role of the PAF antagonist. The high-affinity water-soluble PAF antagonist WEB 2170 [25,26] clearly had an effect, decreasing cell proliferation (as measured by [ 3 H]-thymidine incorporation) by 35% and the production of IgM and IgG by the isolated tonsillar cells by 45 to 75%. This was seen over doses ranging from 10 -6 to 10 -8 M; doses exceeding this were ineffective.…”

Metal-Free Synthesis of 1,3,4-Oxadiazoles from N′-(Arylmethyl)hydrazides or 1-(Arylmethyl)-2-(arylmethylene)hydrazines

“…Others display insecticidal 8 or herbicidal 9 properties. Furthermore, 2,5-dialkyl-1,3,4-oxadiazoles can inhibit platelet aggregation 10 and have attracted interest from medicinal chemists for their use as bioisosteres for carboxylic acids, esters, or carboxamides. 11 Examples of medicinally important compounds that contain a 1,3,4-oxadiazole moiety include raltegravir, 4 zibotentan, 5 nesapidil, 6 and furamizole 12 (Figure 1).…”

Current Scenario of 1,4-Diazepines as Potent Biomolecules-A Mini Review

“…Among the series of the compounds, compound (110) showed to be a specific antagonist for PAF receptor and is currently under clinical trials. Many structurally related analogs have been reported to possess antiplatelet activity [149][150][151][152][153]. GPIIbIIIa antagonists inhibit the adhesive and aggregatory function of platelets by binding to platelet receptor GPIIbIIIa [145].…”