RESUMEN
[figure: see text] Substituted 2,3,3a,4,5,7a-hexahydrobenzo[d]isothiazole 1,1-dioxides and 3,4,4a,5,6,8a-hexahydro-2H-benzo[e][1,2]thiazine 1,1-dioxides, novel cyclic sulfonamides, were synthesized by the thermal Diels-Alder reaction of triene derivatives of buta-1,3-diene-1-sulfonic acid amide. The stereochemical outcome of the reaction was determined by NMR spectroscopy and X-ray crystallographic analysis. This chemistry has been used for the synthesis of 2-(4-chlorobenzyl)-5-(1H-imidazol-4-yl)-2,3,3a,4,5,7a-hexahydrobenzo[d] isothiazole 1,1-dioxide, a histamine H3 receptor antagonist.
Asunto(s)
Sulfonamidas/síntesis química , Cristalografía por Rayos X , Antagonistas de los Receptores Histamínicos/síntesis química , Espectroscopía de Resonancia Magnética , Receptores Histamínicos H3/efectos de los fármacos , Sulfonamidas/químicaRESUMEN
In the course of structural explorations around a series of potent CCK2 receptor antagonists, it was noted that simple N-methylation of the indolic N-H in the parent molecule gave rise to behavior in vivo that was consistent with the compound acting as an agonist. Exploration in vitro confirmed this property, and it was shown that the agonist action could be blocked by the reference CCK2 receptor antagonist, L-365,260. Further examples of this type of modification were explored, and a common theme with regard to agonist behavior was uncovered. Some molecular modeling is also presented in an attempt to throw light on the nature of the ligand receptor interactions that may be giving rise to the differing properties of these, apparently, structurally similar molecules.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/síntesis química , Indoles/síntesis química , Receptores de Colecistoquinina/agonistas , Adamantano/química , Adamantano/farmacología , Animales , Benzodiazepinonas/farmacología , Unión Competitiva , Corteza Cerebral/metabolismo , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Ligandos , Ratones , Modelos Moleculares , Pentagastrina/farmacología , Compuestos de Fenilurea/farmacología , Ensayo de Unión Radioligante , Ratas , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/antagonistas & inhibidores , Receptores de Colecistoquinina/metabolismo , Estereoisomerismo , Estómago/efectos de los fármacosRESUMEN
A novel series of nonpeptide CCK(2) receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (5) was used as a chemical template. This uncommon ring system was obtained in a highly substituted form and in high yield by ozonolysis of the enamine bond of 1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indole derivatives (4), in which the configuration of the substituents was established stereoselectively via the Pictet-Spengler reaction. Further structural manipulation was guided by molecular modeling through comparison of fieldpoint-based structures of candidate compounds with a selected low-energy conformation of the representative CCK(2) receptor antagonist 5-[[[(1S)-[[(3, 5-dicarboxyphenyl)amino]carbonyl]-2-phenylethyl]amino]carbonyl]-6- [[( 1-adamantylmethyl)amino]carbonyl]indole (JB93182 (3)). By this approach compounds such as (3R, 5S)-4-acetyl-3-(1-adamantyl)methyl-1-(2-chlorobenzyl)-5-carboxymet hyl aminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (32) were prepared. Compound 32 behaved as a competitive CCK(2) receptor antagonist in vitro as judged by its inhibition of pentagastrin-stimulated acid secretion in an isolated, lumen-perfused, immature rat stomach assay (pK(B) = 6.74 +/- 0.27) and by its displacement of [(125)I]CCK-8S from CCK(2) sites in mouse cortical homogenates (pK(i) = 6.99 +/- 0.05). Compound 32 was 100-fold selective for CCK(2) over CCK(1) receptors based on the affinity estimate obtained in a guinea pig pancreas radioligand binding assay (pK(i) = 5.0).
Asunto(s)
Quinonas/síntesis química , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Unión Competitiva , Diseño de Fármacos , Ácido Gástrico/metabolismo , Cobayas , Técnicas In Vitro , Modelos Moleculares , Páncreas/metabolismo , Quinonas/química , Quinonas/farmacología , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
4-Chlorophenylmethanesulfonamide and (4-chlorobenzyl)sulfamide derivatives of histamine homologues were prepared and found to be potent and selective histamine H3 receptor antagonists. High receptor affinity and low differences in the data from the bioassays were achieved with the imidazol-4-ylbutyl analogues.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Histamina/análogos & derivados , Naftalenos/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Sulfonamidas/síntesis química , Animales , Diseño de Fármacos , Cobayas , Antagonistas de los Receptores Histamínicos/farmacología , Íleon/efectos de los fármacos , Íleon/metabolismo , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Naftalenos/farmacología , Sulfonamidas/farmacologíaRESUMEN
Histamine was converted to a selective histamine H3-receptor antagonist by capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor affinity and lower variability in the data from the various bioassays were achieved with the 2-naphthalensulfonamides of histamine homologues.
Asunto(s)
Diseño de Fármacos , Antagonistas de los Receptores Histamínicos/síntesis química , Imidazoles/síntesis química , Receptores Histamínicos H3/química , Sulfonamidas/síntesis química , Animales , Cobayas , Cinética , Modelos QuímicosRESUMEN
A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.
Asunto(s)
Compuestos Policíclicos/farmacología , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Perros , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Compuestos Policíclicos/química , Ratas , Receptor de Colecistoquinina B , Especificidad de la EspecieRESUMEN
We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.