RESUMEN
The discovery of the nonpeptide angiotensin II (AII) receptor antagonist losartan, previously called DuP 753, has stimulated considerable interest in the synthesis of novel analogs of this compound. Our efforts in this area have resulted in the discovery of dihydropyrimidines as potent AII receptor antagonists. The chemistry leading to this novel class of AII antagonists and their biological properties are reported in this publication. Structure-activity studies showed that a variety of substituents are tolerated on the dihydropyrimidine ring, indicating that the AII receptor is permissive in accepting this region of the nonpeptide antagonists. As reported for imidazole-based AII antagonists, the tetrazolyl dihydropyrimidine analogs were found to be more potent than the corresponding carboxylic acids. Our studies show that dihydropyrimidine analogs 2-butyl-4-chloro-1,6-dihydro-6-methyl-1-[[2'-(1H-tetrazol-5-yl)[1, 1'-biphenyl]-4-yl]methyl]pyrimidine-5-carboxylic acid, ethyl ester (Ki = 8.3 nM), 2-butyl-4-chloro-1,6-dihydro-6-methyl-1- [[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5- pyrimidinecarboxylic acid (Ki = 1.0 nM), and 2-butyl-6-chloro-1,4-dihydro-4,4-dimethyl-1-[[2'-(1H-tetrazol-5-yl )[1,1'- biphenyl]-4-yl]methyl]-5-pyrimidinecarboxylic acid, ethyl ester (Ki = 1.1 nM), display affinities for the AII receptor which are comparable to or better than losartan (Ki = 9.0 nM). One of these derivatives, 2-butyl-4-chloro-1,6-dihydro-6-methyl-1-[[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]pyrimidine-5-carboxylic acid, ethyl ester, showed antihypertensive activity on oral administration to spontaneously hypertensive rats. These results demonstrate that the imidazole of losartan can be successfully replaced with a dihydropyrimidine ring.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antihipertensivos/síntesis química , Pirimidinas/síntesis química , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Imidazoles/farmacología , Losartán , Masculino , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Tetrazoles/farmacologíaRESUMEN
We have examined a series of novel dihydropyrimidine calcium channel blockers that contain a basic group attached to either C5 or N3 of the heterocyclic ring. Structure-activity studies show that a 1-(phenylmethyl)-4-piperidinyl carbamate moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart potent and long-acting antihypertensive activity in vivo. One of these compounds (11) was identified as a lead, and the individual enantiomers 12a (R) and 12b (S) were synthesized. Two key steps of the synthesis were (1) the efficient separation of the diastereomeric ureido derivatives 29a/29b and (2) the high-yield transformation of 2-methoxy intermediates 30a/30b to the (p-methoxybenzyl)thio intermediates 31a/31b. Chirality was demonstrated to be a significant determinant of biological activity, with the dihydropyridine receptor recognizing the enamino ester moiety (12a) but not the carbamate moiety (12b). Dihydropyrimidine 12a is equipotent to nifedipine and amlodipine in vitro. In the spontaneously hypertensive rat, dihydropyrimidine 12a is both more potent and longer acting than nifedipine and compares most favorably with the long-acting dihydropyridine derivative amlodipine. Dihydropyrimidine 12a has the potential advantage of being a single enantiomer.
Asunto(s)
Antihipertensivos/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Piperidinas/síntesis química , Pirimidinas/síntesis química , Amlodipino , Animales , Antihipertensivos/química , Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Cristalización , Hipertensión/tratamiento farmacológico , Masculino , Estructura Molecular , Nifedipino/análogos & derivados , Nifedipino/uso terapéutico , Piperidinas/química , Piperidinas/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Conejos , Ratas , Ratas Endogámicas SHR , Estereoisomerismo , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacos , Difracción de Rayos XRESUMEN
In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2 microM) dihydropyrimidine calcium channel blocker 5, we carried out drug metabolism studies in the rat and found 5 is metabolized to compounds 6-10. Two of the metabolites, 6 (IC50 = 16 nM) and 7 (IC50 = 12 nM), were found to be responsible for the antihypertensive activity of compound 5. Potential metabolism of 6 into 7 in vivo precluded our interest in pursuing compounds related to 6. Structure-activity studies aimed at identifying additional aryl-substituted analogues of 7 led to 17g,j,p with comparable potential in vivo, though these compounds were less potent than 7 in vitro. To investigate the effects of absolute stereochemistry on potency, we resolved 7 via diastereomeric ureas 19a,b, prepared from 18 by treatment with (R)-alpha-methylbenzylamine. Our results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR. The in vivo potency and duration of 20a is comparable to the long-acting dihydropyridine amlodipine. The superior oral antihypertensive activity of 20a compared to that of previously described carbamates 2 (R2 = COOEt) could be explained by its improved oral bioavailability, possibly resulting from increased stability of the urea functionality.
Asunto(s)
Antihipertensivos/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Fenómenos Químicos , Química , Masculino , Conejos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
Substituted 1,2,3,4-tetrahydroaminonaphthols were found to be calcium channel blockers with antihypertensive properties. These compounds also possessed adrenergic beta-receptor blocking activity. From the structure-activity studies, no clear correlation emerged between the in vitro calcium channel blocking activity and the acute anti-hypertensive activity in cannulated spontaneously hypertensive rats. Extensive pharmacological testing of selected compounds indicated that aminonaphthols are antihypertensive agents with many pharmacological properties. The relative contribution of various pharmacological actions toward the observed antihypertensive activity is unclear. Since the clinically useful calcium channel blocker verapamil is structurally related to these compounds, one of the aminonaphthols, trans-3-[(3,3-diphenylpropyl)amino]-1,2,3,4-tetrahydro-6,7 -dimethoxy-2-naphthalenol (12), was compared with verapamil for calcium channel blocking activity, adrenergic blocking activity, and catecholamine-depleting activity. Both compounds were found to be equipotent in these test systems.