The Pharmacological Characterization of FK 739, a New Angiotensin II-Receptor Antagonist

Abstract

ABSTRACT-The pharmacological properties of FK 739, a new angiotensin 11-receptor antagonist, were ex amined. FK 739 inhibited the specific binding of [125I1-angiotensin II to rat aortic smooth muscle cell mem brane with an IC50 value of 8.6 nM, but did not displace the specific binding of [1151] -angiotensin II to bovine cerebellum membrane. In isolated helical strips of rabbit aorta, FK 739 shifted the concentration response curve of angiotensin II-induced contraction in parallel to the right, and the values of the slope and pA2 were 1.06 and 8.45, respectively. In in vivo studies, oral administration of FK 739 at 10 mg/kg sig nificantly inhibited the angiotensin I-induced pressor response in normotensive rats and dogs, and it caused a fall of mean blood pressure in renal hypertensive rats and dogs. In spontaneously hypertensive rats, FK 739 at 32 and 100 mg/kg significantly decreased the mean blood pressure in a dose-dependent manner. Additionally, we studied whether FK 739 would cause side effects such as dry cough, like other ACE in hibitors did. Oral administration of FK 739 (10 and 32 mg/kg) did not affect the capsaicin-induced bron chial edema. On the other hand, captopril (10 mg/kg) significantly enhanced capsaicin-induced bronchial edema. These results indicate that FK 739 is a potent and competitive antagonist for AT,-type receptors, and suggest that FK 739 might be a safe and useful agent for the treatment of hypertension in clinical trials.

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

“…FK739 (Fujisawa) is a selective and competitive AT 1 antagonist (AT 1 IC 50 ) 0.6 nM, rat aorta; pA 2 ) 8.45, rabbit aorta). 133 FK739 dosed at 10 mg/kg, po, was effective in blocking the Ang II-induced pressor response in normotensive rats and dogs and in decreasing blood pressure in RHR and renal hypertensive dogs. In SHR, FK739 at 32 and 100 mg/kg, po, reduced BP in a dosedependent manner.…”

“…Two additional imidazopyridines, FK739 and E4177, were placed into clinical evaluation in Japan. FK739 (Fujisawa) is a selective and competitive AT 1 antagonist (AT 1 IC 50 = 0.6 nM, rat aorta; p A 2 = 8.45, rabbit aorta) . FK739 dosed at 10 mg/kg, po, was effective in blocking the Ang II-induced pressor response in normotensive rats and dogs and in decreasing blood pressure in RHR and renal hypertensive dogs.…”

Angiotensin II Type 1 Receptor Antagonist Downregulates Nonmuscle Myosin Heavy Chains in Spontaneously Hypertensive Rat Aorta

“…The nonpeptide AT 1 receptor antagonist FK-739 (FK) 13 and enalapril (EN) were gifts of Fujisawa Pharmaceutical Co, Ltd (Osaka, Japan) and Banyu Pharmaceutical Co, Ltd (Tokyo, Japan), respectively. Specific antibodies against SM-1, SM-2, NMHC-A, and NMHC-B 5,14 were the kind gift of Drs Robert S. Adelstein, Hiroshi Ito, and Christine A. Kelly, and purified turkey gizzard SM myosin for SM-1 and SM-2 and purified human platelet myosin for NMHC-A were the kind gift of James R. Sellers, National Institutes of Health (Bethesda, Md).…”