Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
J Med Chem ; 56(8): 3247-56, 2013 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-23517501

RESUMEN

The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic ß-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.


Asunto(s)
Células Secretoras de Insulina/efectos de los fármacos , Canales KATP/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Tiadiazinas/síntesis química , Animales , Benzotiadiazinas/síntesis química , Benzotiadiazinas/farmacología , Diazóxido/análogos & derivados , Diazóxido/farmacología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Parasimpatolíticos/farmacología , Relación Estructura-Actividad , Tiadiazinas/farmacología
2.
J Med Chem ; 54(9): 3188-99, 2011 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-21428460

RESUMEN

The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic ß-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic ß-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.


Asunto(s)
Benzotiadiazinas/síntesis química , Diazóxido/análogos & derivados , Diazóxido/síntesis química , Canales KATP/fisiología , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Benzotiadiazinas/farmacología , Diazóxido/farmacología , Femenino , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Activación del Canal Iónico , Modelos Moleculares , Conformación Molecular , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Útero/efectos de los fármacos , Útero/fisiología
3.
J Med Chem ; 48(15): 4990-5000, 2005 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-16033278

RESUMEN

A series of 6,7-disubstituted 4H-1,2,4-benzothiadiazine 1,1-dioxides bearing a short alkylamino side chain in the 3-position were synthesized. These compounds were tested on rat pancreatic islets and on rat aorta rings. In vitro data indicated that in most cases substitution in the 6 and the 7 positions increased their activity as inhibitors of insulin secretion, while the myorelaxant potency of the drugs was maintained or enhanced according to the nature of the substituent in the 7-position. The presence of either chlorine or bromine atoms in the 6 and 7 positions did not improve the apparent selectivity of the drugs for the pancreatic tissue. By contrast, the introduction of one or two fluorine atoms, as well as the presence of a methoxy group in the 7-position, generated potent and selective inhibitors of insulin release. Radioisotopic and fluorimetric experiments performed with the most potent compound inhibiting insulin release (34, BPDZ 259, 6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide) confirmed that the drug activated K(ATP) channels. 34 was found to be one of the most potent and selective pancreatic potassium channel openers yet described.


Asunto(s)
Adenosina Trifosfato/fisiología , Benzotiadiazinas/síntesis química , Óxidos S-Cíclicos/síntesis química , Canales de Potasio/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Activación del Canal Iónico , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Especificidad de Órganos , Ratas , Ratas Wistar , Relación Estructura-Actividad
4.
J Med Chem ; 48(10): 3492-503, 2005 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-15887958

RESUMEN

The present work explored 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides diversely substituted in the 7-position. Those compounds, structurally related to previously described potassium channel openers such as the benzothiadiazine dioxide BPDZ 73, were tested as putative K(ATP) channel activators on the pancreatic endocrine tissue and on the vascular smooth muscle tissue. The nature of the substituent introduced in the 7-position as well as the nature of the alkylamino side chain in the 3-position strongly affected both potency and tissue selectivity of 4H-1,2,4-benzothiadiazine 1,1-dioxides. Thus, compounds bearing in the 7-position a methyl or a methoxy group or devoid of a substituent in this position, and bearing an ethyl, an isopropyl, or a cyclobutylamino group in the 3-position were found to be potent and selective inhibitors of insulin release from rat pancreatic B-cells (i.e. 10a, 10b, 12b, 12d, 22c). In contrast, 3-alkylamino-7-trifluoromethyl- (20a-c) and 3-alkylamino-7-pentyl-4H-1,2,4-benzothiadiazine 1,1-dioxides (11a,b) expressed a marked myorelaxant activity on rat aorta ring. Among the latter compounds, the 3-alkylamino-7-pentyl derivative (11a) showed a clear selectivity for the vascular smooth muscle tissue. The present work gives new insights into the role of the substituent in both the 7- and the 3-position for the design of 4H-1,2,4-benzothiadiazine 1,1-dioxide potassium channel openers exhibiting different tissue selectivity profiles.


Asunto(s)
Adenosina Trifosfato/fisiología , Benzotiadiazinas/síntesis química , Canales de Potasio/agonistas , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Activación del Canal Iónico , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vasodilatadores/síntesis química , Vasodilatadores/química , Vasodilatadores/farmacología
5.
J Med Chem ; 48(2): 614-21, 2005 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-15658874

RESUMEN

Five series (ureas, thioureas, carbamates, sulfonylureas, and amides) of 4,6-disubstituted-2,2-dimethylchromans structurally related to cromakalim were prepared and evaluated, as putative ATP-sensitive potassium channel activators, on rat pancreatic islets and rat aorta rings. The biological data indicate that most compounds were, like the reference molecule cromakalim, more active on the vascular smooth muscle tissue (myorelaxant effect on 30 mM KCl induced contractions of rat aorta rings) than on the pancreatic tissue (inhibition of 16.7 mM glucose induced insulin release from rat pancreatic islets). However, some drugs (8h, 8i, 9f, 9g, 9h, and 9i) markedly inhibited insulin release and exhibited an activity equivalent or greater than that of diazoxide. Compounds 9h and 9i were also found to be more active on pancreatic beta-cells than on vascular smooth muscle cells. Last, the amide 6b was selected in order to examine its mechanism of action on vascular smooth muscle cells. Pharmacological results suggest that the compound acted as a K(ATP) channel opener. In conclusion, the present data indicate that appropriate structural modifications can generate dimethylchromans with pharmacological profiles different from that of cromakalim.


Asunto(s)
Cromanos/síntesis química , Cromakalim/química , Insulina/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Islotes Pancreáticos/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Vasodilatadores/síntesis química , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Cromanos/química , Cromanos/farmacología , Cromakalim/farmacología , Técnicas In Vitro , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Músculo Liso Vascular/fisiología , Canales de Potasio/fisiología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vasodilatadores/química , Vasodilatadores/farmacología
6.
J Med Chem ; 46(15): 3342-53, 2003 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-12852765

RESUMEN

3-(Alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides were synthesized, and their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators diazoxide and pinacidil. Structure-activity relationships indicated that an improved potency and selectivity for the pancreatic tissue was obtained by introducing a fluorine atom in the 7-position and a short linear (preferably ethyl) or cyclic (preferably cyclobutyl) hydrocarbon chain on the nitrogen atom in the 3-position. By contrast, strong myorelaxant activity was gained by the introduction of a halogen atom different from the fluorine atom in the 7-position and a bulky branched alkylamino chain in the 3-position. Thus, 3-(ethylamino)-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide (11) expressed a marked inhibitory activity on pancreatic B-cells (IC(50) = 1 microM) associated with a weak vasorelaxant effect (ED(50) > 300 microM), whereas 7-chloro-3-(1,1-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide (27), which was only slightly active on insulin-secreting cells (IC(50) > 10 microM), was found to be very potent on vascular smooth muscle cells (ED(50) = 0.29 microM). Radioisotopic and electrophysiological investigations performed with 7-chlorinated, 7-iodinated, and 7-fluorinated 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides confirmed that the drugs activated K(ATP) channels. The present data revealed that subtle structural modifications of 3-(alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides can generate original compounds activating K(ATP) channels and exhibiting different in vitro tissue selectivity profiles.


Asunto(s)
Benzotiadiazinas , Diazóxido/análogos & derivados , Diazóxido/síntesis química , Islotes Pancreáticos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Diazóxido/química , Diazóxido/farmacología , Femenino , Glucosa/farmacología , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Activación del Canal Iónico , Islotes Pancreáticos/metabolismo , Isomerismo , Conformación Molecular , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Especificidad de Órganos , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Relación Estructura-Actividad , Xenopus laevis
7.
Biol Chem ; 383(11): 1759-68, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12530541

RESUMEN

A series of 2-alkyl-3-alkylamino-2H-benzo- and 2-alkyl-3-alkylamino-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides, structurally related to BPDZ 44 and BPDZ 73, two potent pancreatic B-cells K+ATP channel openers, were synthesized and tested on rat pancreatic islets (endocrine tissue) as well as on rat aorta rings (vascular smooth muscle tissue). Alkylation of the 2-position led to double bond tautomerization and formation of compounds with a 2H-conformation. In contrast to the previously described pyridothiadiazine dioxides, such as BPDZ 44, and 7-chlorobenzothiadiazine dioxides, such as BPDZ 73, the 2-alkyl-substituted analogs were found to be poorly active on the insulin releasing process although most drugs exhibited a vasorelaxant activity. As a result, the new 2-alkyl-substituted pyridinic compounds expressed a selectivity profile (vascular smooth muscle tissue vs pancreatic tissue) opposite to that of their non-alkyl-substituted counterparts, i.e. BPDZ 44. Additional investigations revealed that, in contrast to their non 2-alkyl-substituted analogs, the most interesting 2-methyl-substituted derivatives did not express the pharmacological profile of classical K+ATP channel openers. The pharmacological results rather suggest that alkylation of the 2-position of the thiadiazine ring led to drugs that could act as Ca2+ channel blockers rather than as potassium channel openers.


Asunto(s)
Alcanos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Diazóxido/farmacología , Canales de Potasio/agonistas , Tiadiazinas/farmacología , Transportadoras de Casetes de Unión a ATP , Alcanos/síntesis química , Animales , Aorta Torácica/efectos de los fármacos , Bloqueadores de los Canales de Calcio/síntesis química , Diazóxido/síntesis química , Técnicas In Vitro , Indicadores y Reactivos , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Canales KATP , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio de Rectificación Interna , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiadiazinas/síntesis química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA