Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.

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The cardiovascular responses to intravenous (i.v.) injection of natural tachykinins, substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and selective tachykinin (NK) receptor agonists, [Sar9, Met(O2)11]SP, [βAla8]NKA(4–10), [MePhe7]NKB and senktide were assessed in conscious, freely moving, guinea‐pigs. SP and [Sar9, Met(O2)11]SP (1–1000 pmol kg−1) induced dose‐dependent decreases in mean arterial blood pressure (MAP) accompanied by increases in heart rate (HR). NKA evoked only weak hypotensive effects at high doses (3000 pmol kg−1) whereas [βAla8]NKA(4–10) (1–3000 pmol kg−1) had no effects. By contrast, NKB [MePhe7]NKB (1–10000 pmol kg−1) and senktide (1–1000 pmol kg−1), produced dose‐related hypertensive effects with the following rank order of potency: senktide > [Me‐Phe7]NKB > NKB. Bradycardia occurred simultaneously with the increases in arterial pressure. The pressor response to intravenous injection of senktide (300 pmol kg−1) was partially reduced by pretreatment with prazosin (0.71 μmol kg−1), or clonidine (0.38 μmol kg−1) and was completely inhibited by the combination of the two compounds. Atropine (1.5 μmol kg−1) suppressed the decrease in HR induced by senktide without altering the blood pressure response. These findings suggest that the blood pressure response to senktide is an indirect effect mediated by noradrenaline released from sympathetic nerve endings, whereas the bradycardia is of vagal reflex origin. SR 142801, ((S)‐(N)‐(1‐(3‐(1‐benzoyl‐3‐(3, 4‐dichlorophenyl) piperidin‐3‐yl) propyl)‐4‐phenyl‐piper‐idin‐4‐yl)‐N‐methylacetamide), a potent and specific non‐peptide NK3 receptor antagonist dose‐dependently (0.46‐4.6 μmol kg−1, i.v.; 4.6–46 μmol kg−1, p.o.) inhibited the cardiovascular effects of senktide and displayed a long‐lasting inhibitory effect after oral administration. By contrast, SR 142806 (4.6 μmol kg−1, i.v.), the (R)‐enantiomer of SR 142801 had no effect on the responses to senktide. SR 142801 at a high dose (15 μmol kg−1, i.v.) was inactive toward the [Sar9, Met(O2)11]SP‐induced hypotension. SR 142801 did not modify MAP in conscious guinea‐pigs both after i.v. (4.6 and 15 μmol kg−1) and oral (46 and 150 μmol kg−1) administration, showing a lack of agonistic properties. However, a slight reduction in HR was observed only after i.v. injection. In conclusion, these results show evident differences in the functional role of tachykinin receptors in the peripheral control of the cardiovascular system. Furthermore, a clear pressor effect of senktide, which was selectively blocked by SR 142801, was observed in conscious guinea‐pigs. Hence, this antagonist appears suitable for investigating the functional role of NK3 receptors.

Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. SR 47436 at 10 mg kg−1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg−1, indicating that a maximal hypotensive effect had already been obtained. A single oral dose of SR 47436 (10 mg kg−1) caused a sustained hypotension and a marked inhibition of the AII‐induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug (t1/2 ≅ 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. Although a fair correlation between individual plasma drug concentrations and inhibition of AII‐induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. Basal arterial pressure and AII‐induced pressor response were not affected by blood samplings. These results suggest that SR 47436 is an effective and long lasting AT1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious blocker of the RAS in man and suitable for once‐a‐day dosing.

SSR149744C (2-butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate isopropyl fumarate) is a new noniodinated benzofuran derivative structurally related to amiodarone and dronedarone that is currently undergoing clinical trials as an antiarrhythmic agent. As SSR149744C exhibits electrophysiological and hemodynamic properties of class I, II, III, and IV antiarrhythmic agents, the aim of this study was to evaluate its acute intravenous (IV) or oral (PO) antiarrhythmic activities in in vitro and in vivo animal models of atrial and ventricular arrhythmias. In vagally induced atrial fibrillation (AF) in anesthetized dogs, SSR149744C (3 and 10 mg/kg IV) terminated AF in all 7 dogs and prevented reinduction in 4 out of 7 dogs; effective refractory periods of right atrium were dose-dependently and frequency-independently lengthened. In low-K+ medium-induced AF models, SSR149744C (0.1 to 1 microM) prevented AF in isolated guinea pig hearts in a concentration-dependent manner. At the ventricular level, SSR149744C (0.1 to 10 mg/kg IV and 3 to 90 mg/kg PO) prevented reperfusion-induced arrhythmias in anesthetized rats with a dose-effect relationship, and, at doses of 30 to 90 mg/kg PO, it reduced early (0-24 hours) mortality following permanent left coronary artery ligature in conscious rats. The present results show that SSR149744C is an effective antiarrhythmic agent in atrial fibrillation and in ventricular arrhythmias. Like amiodarone and dronedarone, its efficiency in these animal models of arrhythmias is likely be related to its multifactorial mechanism of action.