A series of 51 6-arylpyrido[2,3-d]pyrimidin-7-amine derivatives was prepared and evaluated for antihypertensive activity in the conscious spontaneously hypertensive rat. A number of these compounds, notably 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine (36), lowered blood pressure in these rats in a gradual and sustained manner to normotensive levels at oral doses of 10-50 mg/kg. Normalized blood pressure levels could then be maintained by single daily oral doses. The effect of structural variation in the 6-aryl group and in the 2 and 4 positions of the pyridopyrimidine ring on activity is reported and discussed.
The effect of acylation with a variety of acids on the antihypertensive activity of 6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidine-7-amine (1) is reported, and structure-activity relationships are discussed. Although several of the compounds show good oral antihypertensive activity in the conscious, spontaneously hypertensive rat (SHR), their activity profile appears to differ from 1 in that the onset of action is shortened at comparable blood pressure lowering doses, and the magnitude of effect is considerably greater at higher doses. A variety of urea, thiourea, guanidine, and amidine analogues also were prepared. Although many of these derivatives showed some antihypertensive effects when dosed orally to SHR, this activity was weaker and of shorter duration than that obtained with 1. Aqueous solubilities and hydrolytic stabilities for four of the more active compounds were measured and suggest that these do not function as prodrugs of 1.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.