Yoshihiro Hashimoto, Rikiya Ohashi, Koichi Minami and Hiroshi Narita
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2 - 2 - 50,
Kawagishi, Toda, Saitama 335 - 8505, Japan
Abstract: 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 potentialy cause orthostatic hypotension. In this report,
we examined effects of TA-606 o(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 hydrochloridep, 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.
Keywords: TA-606, Angiotensin II receptor antagonist, Conscious dog,
Renal hypertension,
Orthostatic hypotension