Long-acting dihydropyridine calcium antagonists. 5. Synthesis and structure-activity relationships for a series of 2-[[(N-substituted-heterocyclyl)ethoxy]methyl]-1,4-dihydropyridine calcium antagonists.

The synthesis of a series of 1,4-dihydropyridines which have N-linked heterocycles at the terminus of an ethoxymethyl chain at the 2-position is described. The calcium antagonist activity on rat aorta of this class of DHPs is compared with their negative inotropic activity as determined by using a Langendorff-perfused guinea pig heart model. The compounds examined show a wide range of selectivity for vascular over cardiac tissue, with those analogues which possess an amide group at the terminus of the 2-substituent proving the most selective. From the in vitro data obtained for a series of 1,2,3-triazoles, it is possible to conclude that the SARs for binding to the calcium channels in vascular and cardiac tissue are different. One of the compounds, 2-amino-1-[2-[[4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5- (methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]-4( 3H)- imidazolone (20b, UK-55,444), was identified as a potent (IC50 = 8 x 10(-9) M) calcium antagonist which is 40-fold selective for vascular over cardiac tissue and which has a significantly longer duration of action (greater than 3 h) than nifedipine in the anesthetized dog on intravenous administration.

Long-acting dihydropyridine calcium antagonists. 4. Synthesis and structure-activity relationships for a series of basic and nonbasic derivatives of 2-[(2-aminoethoxy)methyl]-1,4-dihydropyridine calcium antagonists.

The preparation of a series of 1,4-dihydropyridines (DHPs) which have polar, acyclic, nonbasic substituents on an ethoxymethyl chain at the 2-position is described. In addition, in order to assess the effects of incorporating a basic center into DHPs of this type, a series of glycinamides were also prepared. The calcium antagonist activity on rat aorta of both these classes of DHP is compared with their negative inotropic activity as determined by using a Langendorff perfused guinea pig heart model. A number of the compounds evaluated have activity of the same order as nifedipine although those with more extended substituents have lower potency, particularly when a basic substituent is present. The compounds examined displayed a wide variation in selectivity for vascular over cardiac tissue. A number of structure-activity relationship trends were identified and possible explanations to account for the differences in selectivity observed are advanced. One of the compounds, 2-[[2-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6- methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]amino]acetamide (26, UK-51,656), was identified as a potent (IC50 = 4 x 10(-9) M) calcium antagonist which is 20-fold selective for vascular over cardiac tissue and which has a markedly longer duration of action (greater than 5 h) than nifedipine in the anesthetized dog on intravenous administration. The pharmacokinetic half-life of 26 was established as 4.7 h and possible explanations are advanced to account for 26 having a shorter plasma half-life than amlodipine and a longer plasma half-life than felodipine.

Pharmacologic profile of amlodipine.

Amlodipine is a potent calcium antagonist, inhibiting Ca2+-induced contractions of depolarized rat aorta with an IC50 of 1.9 nM. Unlike nifedipine, it displayed very slow association and dissociation with the calcium channel. The ability of amlodipine to inhibit Ca2+-induced contractions was strongly dependent on the K+ concentration present before the contraction, suggesting marked voltage dependence of action. Radioligand-binding studies in cardiac membrane preparations suggested that amlodipine may interact directly with both 1,4-dihydropyridine and diltiazem-binding sites on the calcium channel. Hemodynamic studies in anesthetized and conscious dogs showed that amlodipine is a coronary and peripheral vasodilator with a slow onset and long duration of effect, even when given by intravenous injection; the reflex stimulation of cardiac output, heart rate and myocardial contractility induced by amlodipine was attenuated by propranolol, but no marked negative inotropic or dromotropic effects were observed. Amlodipine was an effective oral antihypertensive agent in rat and dog models of hypertension, and its 24-hour duration of action in hypertensive dogs correlated well with its long plasma half-life in this species. The natriuretic properties displayed by amlodipine may contribute to its use as a first-line drug for the treatment of hypertension.

Long-acting dihydropyridine calcium antagonists. 3. Synthesis and structure-activity relationships for a series of 2-[(heterocyclylmethoxy)methyl] derivatives.

The preparation of 1,4-dihydropyridines containing (heterocyclylmethoxy)methyl groups in the 2-position is described and the structural identification of certain of the compounds using 1H NMR spectroscopic methods is reported. The calcium antagonist activity of the compounds on rat aorta is listed and is compared with the negative inotropic potency as determined by using a Langendorff-perfused guinea pig heart model. Several compounds are more potent than nifedipine and show greater selectivity for the vasculature over the heart. One compound, 2-[(2-amino-4-hydroxypyrimidin-6-yl)methoxy]-4- (2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl- 1,4-dihydropyridine (27, UK-56,593), was identified as a potent (IC50 = 1.6 x 10(-9) M), tissue-selective calcium antagonist which proved to have a markedly longer duration of action (greater than 4.5 h) than nifedipine in the anesthetized dog on intravenous administration.

The hemodynamic properties of amlodipine in anesthetised and conscious dogs: comparison with nitrendipine and influence of beta-adrenergic blockade.

The hemodynamic actions of the new dihydropyridine calcium-channel blocker amlodipine were assessed and compared with those of nitrendipine using anesthetised dogs and were also investigated in conscious dogs with and without beta-adrenergic blockade. After bolus intravenous administration, amlodipine (25 to 1600 micrograms/kg) or nitrendipine (1 to 128 micrograms/kg) was administered to anesthetised dogs at 30-minute intervals, caused dose-related reductions in systemic and coronary vascular resistances with corresponding increases in cardiac output and coronary flow. Nitrendipine, unlike amlodipine, caused marked acute hypotension. The onset of action of amlodipine was markedly slower than that of nitrendipine, and effects were maintained for 30 minutes--recovery from nitrendipine was largely complete at 30 minutes. In conscious dogs, amlodipine (250, 500, 1000 micrograms/kg IV) caused dose-related reductions in systemic vascular resistance that approached maximum within 5 minutes and persisted for over 4 hours. Reflex increases in heart rate, cardiac output, and cardiac contractility were attenuated by prior treatment with propranolol, resulting in earlier and greater falls in blood pressure, but no marked adverse effects on cardiac contraction or conduction. In the absence of propranolol, maximum falls in blood pressure occurred 3 to 4 hours after the dose, possibly as a result of the changed baroceptor sensitivity induced by amlodipine. These results show amlodipine to have the basic hemodynamic profile of other dihydropyridine calcium-channel blockers, but in addition it demonstrates a slower onset and longer duration of action; the reasons behind these pharmacodynamic properties are discussed.

Long acting dihydropyridine calcium antagonists. 2. 2-[2-Aminoheterocycloethoxy]methyl derivatives.

A series of [(2-aminoheterocycloethoxy)methyl]dihydropyridines were prepared as selective coronary vasodilators. Results showed that a wide variety of five- and six-membered heterocycles were acceptable at the 2-position of the dihydropyridine ring and in vitro potency and tissue selectivity was independent of the basicity of these heterocycles. The SAR indicated that activity was optimum when the largest ester group was placed at the 3 rather than 5 position. 2-[[2-[(3-Amino-1H-1,2,4-triazol-5-yl)amino]ethoxy]methyl]-4- (2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl- 1,4-dihydropyridine (3b) (UK-52,831) emerged as a potent (IC50 = 6.3 X 10(-9) M) and tissue-selective calcium channel blocker with a duration of action greater than 7 h in the anaesthetized dog.

Natriuretic activity of amlodipine, diltiazem, and nitrendipine in saline-loaded anesthetized dogs.

The natriuretic effects of amlodipine, diltiazem, and nitrendipine were compared in anesthetized dogs receiving a continuous saline load. Doses of all agents were selected that caused similar degrees of coronary vasodilation (approximately 50% of maximum) but that had only minimal peripheral vasodilator effect. Bolus doses of either saline, amlodipine, or diltiazem were administered intravenously. Because of its short duration of action, nitrendipine was given by infusion for 2 h and its effects were compared with infused vehicle [5% polyethylene glycol (PEG 300)]. Bolus amolodipine (105 micrograms/kg) and infused nitrendipine (1 micrograms/kg/min) had a similar hemodynamic profile of action: Both drugs caused a sustained reduction of coronary vascular resistance (CVR) (131.1 to 77.9 and 124.9 to 76.7 dyn/s/cm-5 at 2 h, respectively), but only slightly reduced systemic vascular resistance, with no significant change in blood pressure. Diltiazem (150 micrograms/kg) caused an initial transient reduction of CVR (141.9 to 77.0), followed by a secondary, more sustained action (100.1 at 180 min). Cumulative sodium excretion, measured 1 h after saline, amlodipine, and diltiazem, was 1.96, 5.11, and 5.74 mEq, respectively, increasing to 4.05, 13.19 (p less than 0.05), and 13.09 (p less than 0.05) at 2 h. Significant increases were maintained for up to 3.5 h. A similar pattern was observed with urine volume. Cumulative sodium excretion was 10.05 and 8.27 mEq for vehicle and nitrendipine, respectively, at the end of the 2-h infusion (NS), increasing to 15.88 and 13.73 mEq 60 min later (NS). Nitrendipine did not increase urine volume in comparison with its vehicle alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors.

Amlodipine was twice as potent as nifedipine at inhibiting Ca2+-induced contractions in depolarised rat aorta (IC50 1.9 nM vs. 4.1 nM) but, unlike nifedipine, displayed a very slow onset of action. Contractions induced by depolarising steps with 45 mM K+ were much less potently blocked by amlodipine (IC50 19.4 nM), whereas the potency of nifedipine was little changed (IC50 7.1 nM). This difference may be explained by a modulated receptor hypothesis, similar to that described for cardiac muscle, in which block of vascular calcium channels by dihydropyridines is enhanced at depolarized membrane potentials, such voltage-dependence only being apparent with a slow-acting drug such as amlodipine. Recovery from amlodipine block of K+-responses in rat portal vein after drug washout was also very slow. Amlodipine and nifedipine blocked phenylephrine-induced contractions of the rat aorta with potencies similar to those against depolarisation-induced responses. Negative inotropic potencies of amlodipine and nifedipine in perfused guinea pig hearts were approximately one-tenth those against Ca2+-induced contractions in rat aorta. Amlodipine caused complete block of guinea pig papillary muscle single-cell slow action potentials at a concentration (5 microM) that had no effect on upstroke velocity of normal, fast potentials but reduced the duration of the plateau phase.

Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents.

A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.

Effect of beta-adrenoceptive blocking agents on the response to bronchoconstrictor drugs in the guinea-pig air overflow preparation. Appendix describing a new modification of the air overflow method.

1. Propranolol augmented the bronchoconstrictor response to methacholine or histamine, recorded by air overflow in the anaesthetized, vagotomized guinea-pig.2. After adrenalectomy, propranolol was still active, though less so than before.3. In the pithed guinea-pig, there was no augmentation of the effect of bronchoconstrictors on air overflow. The action of propranolol could thus be due to the beta-adrenoceptor blockade of compensatory sympathetic bronchodilator activity, as concluded by McCulloch, Proctor & Rand (1967).4. Electrical stimulation of the thoracic region of the spinal cord of the pithed guinea-pig reduced the effect of bronchoconstrictors on air overflow. This reduction could be blocked by propranolol; practolol was much less effective.