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 synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.

No abstract

No abstract

No abstract