RESUMEN
The effect on potency and selectivity of modifications at the C6 position of the cardioprotective K(ATP) opener BMS-180448 (2) is described. Structure-activity studies show that a variety of electron-withdrawing groups (ketone, sulfone, sulfonamide, etc.) are tolerated for cardioprotective activity as measured by EC(25) values for an increase in time to the onset of contracture in globally ischemic rat hearts. Changes made to the sulfonamido substituent indicate that compounds derived from secondary lipophilic amines are preferred for good cardioprotective potency and selectivity. The diisobutyl analogue 27 (EC(25) = 0.04 microM) is the most potent compound of this series. The cardiac selectivity of 27 results from a combination of reduced vasorelaxant potency and enhanced cardioprotective potency relative to the potent vasodilating K(ATP) openers (e.g., cromakalim). The diisobutylsulfonamide analogue 27 is over 4 orders of magnitude more cardiac selective than cromakalim (1). These results support the hypothesis that the cardioprotective and vasorelaxant properties of K(ATP) openers follow distinct structure-activity relationships. The mechanism of action of 27 appears to involve opening of the cardiac K(ATP) as its cardioprotective effects are abolished by the K(ATP) blocker glyburide.
Asunto(s)
Benzopiranos/síntesis química , Cardiotónicos/química , Guanidinas/síntesis química , Corazón/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Canales de Potasio/agonistas , Vasodilatadores/química , Animales , Benzopiranos/química , Benzopiranos/farmacología , Cardiotónicos/farmacología , Gliburida/farmacología , Guanidinas/química , Guanidinas/farmacología , Contracción Muscular/efectos de los fármacos , Ratas , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4. showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.
Asunto(s)
Adenosina Trifosfato/metabolismo , Benzopiranos/química , Corazón/efectos de los fármacos , Canales de Potasio/metabolismo , Animales , Disponibilidad Biológica , Gliburida/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.
Asunto(s)
Agonistas de los Canales de Calcio/síntesis química , Agonistas de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/síntesis química , Dihidropiridinas/farmacología , Animales , Agonistas de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/química , Dihidropiridinas/química , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Conejos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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
To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.
Asunto(s)
Bloqueadores de los Canales de Calcio/síntesis química , Dihidropiridinas , Pirimidinas/síntesis química , Animales , Bloqueadores de los Canales de Calcio/farmacología , Fenómenos Químicos , Química , Masculino , Músculo Liso Vascular/efectos de los fármacos , Pirimidinas/farmacología , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.
Asunto(s)
Bloqueadores de los Canales de Calcio/síntesis química , Pirimidinas/síntesis química , Animales , Fenómenos Químicos , Química , Dihidropiridinas/farmacología , Cobayas , Conformación Molecular , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Nitrendipino/antagonistas & inhibidores , Nitrendipino/metabolismo , Pirimidinas/farmacología , Conejos , Ratas , Ratas Endogámicas SHR , Relación Estructura-ActividadRESUMEN
A series of novel hexahydrothiopyrano[4,3-c]pyrazoles and related analogues were prepared and tested for antiinflammatory activity by using the mouse active Arthus reaction and the delayed hypersensitivity skin reaction in guinea pigs as primary screens. The compounds of most interest, 18 and 28, were further tested in a model of adjuvant-induced arthritis; in this system, both compounds were active when dosed intraperitoneally but failed to produce significant activity when dosed orally at subtoxic doses.