TCV‐116: A New Angiotensin II Type‐1 Receptor Antagonist

Abstract

Key Words: Angiotensin I1 type-1 receptor antagonist--CV-1 1974-hypertension-TCV-1 16The renin-angiotensin system plays an important role in the development and maintenance of hypertension, and in recent years, attempts have been made to treat hypertension by suppressing the renin-angiotensin system (2). Because of their established antihypertensive effect, inhibitors of angiotensin converting enzyme (ACE) are now widely used in patients with hypertension and congestive cardiac failure. However, ACE inhibitors do have some side effects, such as "dry cough" and angioedema, caused by the blocking of bradykinin and substance P degradation (25). The first specific peptidic antagonist of angiotensin I1 (Ang 11), Sar*,Alas-Ang 11, was not suitable for long-term treatment because of the lack of oral bioavailability and inherent agonist activity (21). In the early 1980s, Furukawa and colleagues synthesized some imidazole derivatives that specifically blocked Ang 11-induced vasoconstriction (6,15). Important chemical modification of the initial molecules was then performed, leading to the synthesis of DuP 753 (losartan), an orally active nonpeptide Ang I1 receptor antagonist (3,23,26). DuP 753 is metabolized in vivo to an active compound, EXP3174, to exert Ang I1 receptor antagonistic action.TCV-116 is a newly developed, structurally novel, orally effective, highly potent, and long-acting nonpeptide Ang I1 receptor antagonist with a once-a-day dosing regimen. Like DuP 753, TCV-116 is a prodrug; it is metabolized in vivo to an active compound, CV-1 1974 ( 13,14,20). In various animal models of hypertension TCV-1 16 was demonstrated to exert a more potent and prolonged antihypertensive effect than ACE inhibitors or DuP 753. Its clinical efficacy was, therefore, anticipated (8,11,12). CHEMISTRY TCV-116 was synthesized by Takeda Chemical Industries, Ltd. (Osaka, Japan). The chemical name of TCV-116 is ( + )-1-(cyclohexyloxycarbony1oxy)ethyl 2-ethoxy-l-[[2'-( lH-tetrazo1-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. The corn-

Clinical efficacy and tolerability of candesartan cilexetil

“…42 Preclinical studies suggest that candesartan cilexetil has a cardioprotective effect and is also effective in the prevention and regression of left ventricular hypertrophy (LVH). 10,11 The effect of candesartan cilexetil on regression of LVH has been confirmed in short-term clinical trials. Echocardiography and cine-MRI examination show that treatment with 2-12 mg of candesartan cilexetil once daily for 12 to 24 weeks reduced left ventricular weight by 7.7% to 9.3% in patients with mild to moderate essential hypertension.…”

“…9 Preclinical experiments have revealed that candesartan cilexetil has potent and long-lasting hypotensive effects in spontaneously hypertensive, as well as in renal hypertensive, rats. 10 Prevention of hypertensive organ damage was confirmed in the brain, heart, and kidney of spontaneously hypertensive, stroke-prone (SHR-SP) and DOCA-salt rats, and candesartan cilexetil caused regression of cardiac hypertrophy without deterioration of cardiac function in spontaneously hypertensive and SHR-SP rats. 11,12 In previous preliminary clinical studies we confirmed that candesartan cilexetil has a potent, longlasting angiotensin-antagonistic and antihypertensive action in normal volunteers and in patients with essential hypertension.…”

Angiotensin II receptor pharmacology and AT1-receptor blockers

“…The AUC of candesartan is not significantly affected by food intake. 28,106 T max is reached 3-5 h after oral administration. Serum concentrations (AUC) displayed dose linearity with increasing doses in the therapeutic dose range.…”

“…28,106 Candesartan is mainly eliminated unchanged via urine and bile, and is only to a minor extent inactivated by hepatic metabolism. So far, only one inactive metabolite (CV15959) has been described.…”

CV‐11974: A Nonpeptide Angiotensin II Type 1 Receptor Antagonist

“…TCV-116 is a prodrug, and only its metabolite, CV-I 1974, has significant biological activity (22,29). A review of TCV-I 16 has already been published in this journal (25). …”