Comparative study of TA-606, a novel angiotensin II receptor antagonist, with losartan in terms of species difference and orthostatic hypotension.
Losartan is a prodrug type Angiotensin II (Ang II) AT1-receptor antagonist whose efficacy depends on the oxidase activity of individuals. In addition, losartan affects the normal blood pressure and can potentially cause orthostatic hypotension. In this report, we examined effects of TA-606 [(3-pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H -tetrazole-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridine-4-carboxylate hydrochloride], a prodrug type AT1-receptor antagonist, on the Ang II-induced pressor response and hypertension in a dog model, which is known to have lower oxidase activity than other species, and orthostatic hypotension in the rat tilting model. The results indicated that TA-606 was immediately converted to its active form, 606A, after oral administration, and it demonstrated potent inhibition of the Ang II-induced pressor response in conscious normotensive dogs (0.3-3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K,1C-renal hypertensive dogs (0.3-10 mg/kg, p.o.). These effects of TA-606 were 32 and 30 times more potent than those of losartan, respectively. In addition, EXP3174 (1, 10 mg/kg, i.v.), an active metabolite of losartan, but not 606A (1-30 mg/kg, i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These results suggest that TA-606 is an effective Ang II receptor antagonist without the drawbacks of losartan.
Hashimoto
Y
Y
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Ohashi
R
R
Minami
K
K
Narita
H
H
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D007024:Hypotension, Orthostatic / Q000139:chemically induced*; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity*; D019808:Losartan / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D011355:Prodrugs / Q000494:pharmacology / Q000633:toxicity*; D011725:Pyridines / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013045:Species Specificity; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology / Q000633:toxicity*
C106452:606A compound; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D011355:Prodrugs; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C112300:TA 606; D013777:Tetrazoles; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan