Ro 40–5967: A New Nondihydropyridine Calcium Antagonist

Abstract

Key Words: Ro 40-5967--calcium antagonists-hypertension-coronary heart diseaseCalcium antagonists are now widely used for the treatment of angina pectoris and hypertension (for review, see ref. 25). Despite different chemical structures, they all inhibit the slow Ca2+ inward current (7,15). Three main classes of calcium antagonists have been described: dihydropyridines, represented by nifedipine; phenylalkylamines, represented by verapamil; and benzothiazepines, represented by diltiazem. Each of these compounds has its own advantages and disadvantages. Dihydropyridine-type calcium antagonists are very potent peripheral vasodilators and can therefore produce headache, ankle edema, and reflex tachycardia (24). Verapamil has a very potent negative inotropic effect (29) that makes this compound dangerous in patients with a compromised myocardium (8,27). Diltiazem is also negatively inotropic, can produce severe bradycardia, and has also been shown to increase the mortality of patients with prior myocardial infarction and clinical signs of heart failure (30).Finally, all existing calcium antagonists (except the novel dihydropyridine, amlodipine) have a poor bioavailability due to a large first-pass effect and a rather short half-life requiring slow-release formulation for once-a-day dosing. Therefore, the purpose of the calcium antagonist program at F. Hoffmann-La Roche Ltd, Basel was to find a compound with the following properties: (a) high bioavailability; (b) long half-life, allowing once-a-day dosing; (c) lack of biologically relevant negative inotropism; and (d) no strong peripheral vasodilation in normotensive subjects.Ro 40-5967, a novel calcium antagonist, which was selected in animal experiments, fulfilled these criteria. The first clinical studies confirmed the preclinical findings. CHEMISTRYThe chemical name of Ro 40-5967 (see Fig. 1) is (lS,2S)-2-(2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl)-6-fluoro-1,2,3 ,Ctetrahydro-1 -isopropy1-2-naphthylAddress conespondence and reprint requests to Dr.

Human vascular to cardiac tissue selectivity of L‐ and T‐type calcium channel antagonists

“…One measure is to examine the plasma levels of the drug. Cremers et al (1997) suggested that the therapeutic active plasma concentration (TAPC) was 0.14 mM for verapamil and nifedipine, and 0.87 mM for mibefradil (see Henry, 1980;McAllister & Kirsten, 1982;Clozel et al, 1991). If these plasma concentrations are in equilibrium with the vascular and cardiac calcium channels then our studies suggest that verapamil would give 20 ± 30% relaxation of small arteries but more than 70% inhibition of myocardial force, indicating a preferential e ect on myocardium.…”

“…In assay screens, it showed a selective coronary vasodilating property in Langendor perfused guinea pig isolated heart at 12 fold lower concentrations than required to depress left ventricular pressure. This vascular selectivity was absent for verapamil (Clozel et al, 1991;BuÈ hler et al, 1997). Subsequently, Mishra & Hermsmeyer (1994) showed that in voltage clamp studies in single cells from rat azygos vein, mibefradil had 30 ± 100 times greater potency at halving the barium current for transient T-type calcium channels than for the long opening higher conductance L-type channels.…”

N-Type Calcium Channels Control Sympathetic Neurotransmission in Human Heart Atrium

“…Therefore, the aim of the present study was to examine which types of calcium channels are functionally important in the sympathetic nerve terminals of human cardiac tissue. This question was also addressed in the context of the possibility that the favorable bradycardic influence of the novel calcium channel blocker mibefradil 4,5 might be due to an inhibition of norepinephrine release by inhibiting calcium influx into the cardiac sympathetic nerve terminals. 6 The purpose of the present experiments with mibefradil was to provide evidence for the suggestion that mibefradil inhibits norepinephrine release by blocking calcium channels in the postganglionic sympathetic axon terminals.…”

Potent vasodilatory with minor cardiodepressant actions of mibefradil in human cardiac tissue

“…, Clozel et al, 1991) compared to diltiazem (0.19 mmol l 71 , Henry, 1980) used because of the lack of negative inotropic eect at these concentrations. In addition, it has been shown that chronic treatment with mibefradil potentiated the endothelium-dependent relaxation in the aorta of hypertensive salt sensitive Dahl rats (Boulanger et al, 1994).…”

“…-channel antagonists in the treatment of heart failure patients. TAPC: therapeutic active plasma concentration (diltiazem, nifedipine: Henry (1980); mibefradil: Clozel et al (1991)), IC 25 : drug concentration required to decrease the developed force of contraction by 25% of the basal force of contraction in multicellular muscle strips as well as in isolated coronary artery rings, PAP: isolated, electrically driven, left ventricular muscle strip, CAR: coronary artery rings.…”