PYRIDO[2,3-D]PYRIMIDINE ANGIOTENSIN-II ANTAGONISTS

A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a bi phenylyltetrazole pharmacophore and small alkyl groups at the 2- and i i-positions Of the pyridopyrimidine ring were found to be the most pot ent in an AT(1) receptor binding assay and in blocking the A II presse r response in anesthetized, ganglion-blocked A II-infused rats. (2'-(1 H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl)methyl] pyrido[2,3-d]pyrimidin-7( 6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a;in Goldblatt (2K-1C) rats showed the compound to h ave oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.