IN-VIVO PHARMACOLOGICAL CHARACTERIZATION OF UP-269-6, A NOVEL NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST

UP 269-6, l)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one is a nove l nonpeptide angiotensin II receptor antagonist. In vivo studies were performed to evaluate UP 269-6 for its angiotensin II antagonistic act ion. In pithed rats, i.v. administration of UP 269-6 (0.03-1 mg/kg) sh ifted dose dependently to the right the dose-presser response curve fo r angiotensin II and decreased the maximum response. The angiotensin I I antagonistic effect of UP 269-6 was as potent as that of L-158,809 5 -yl)biphenyl-4-yl]methyl]-imidazo[4,5-b]pyridine) and 10 times more po tent than that of losartan. UP 269-6 antagonized the angiotensin II sy mpathetic-mediated tachycardiac response. UP 269-6 inhibited dose depe ndently the presser response to angiotensin II with an ID50 of 4.5 mu g/kg, i.v. in conscious normotensive dogs. Oral administration of UP 2 69-6 (0.1 to 30 mg/kg) resulted in a dose-dependent and long-lasting i nhibition of the angiotensin II-induced presser response in conscious normotensive rats and dogs. Compared to losartan, UP 269-6 presented a more rapid onset of action. UP 269-6 caused similar angiotensin II an tagonistic effects in rats and dogs but the duration of the effect was greater in dogs than in rats. UP 269-6 did not alter the tachycardiac response to isoproterenol and the presser response to vasopressin. UP 269-6 was demonstrated to be devoid of agonistic properties in rats a nd dogs. Furthermore, UP 269-6 did not induce hypotension and did not cause alteration in heart rate and ECG waveforms in dogs even at a dos e 1000 times higher than the angiotensin II antagonistic effective dos e. These results demonstrate that UP 269-6 is a potent and specific an giotensin II receptor antagonist and does not possess agonistic proper ties.