RESUMEN
BACKGROUND/AIMS: The effectiveness of ursodeoxycholic acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic acid but with similar detergency. METHODS: After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of taurochenodeoxycholic acid was evaluated in bile fistula rats after intraduodenal coinfusion. RESULTS: 6-Fluoro-ursodeoxycholic acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile acids (15% ursodeoxycholic acid). The 6-fluoro analogue prevented the hepatotoxic effects of taurochenodeoxycholic acid. CONCLUSIONS: The results suggest that 6-fluoro-ursodeoxycholic acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.
Asunto(s)
Hepatopatías/prevención & control , Ácido Tauroquenodesoxicólico/efectos adversos , Ácido Ursodesoxicólico/análogos & derivados , Albúminas/metabolismo , Animales , Bilis/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas , Cricetinae , Concentración de Iones de Hidrógeno , Hepatopatías/metabolismo , Masculino , Mesocricetus , Unión Proteica , Ratas , Ratas Sprague-Dawley , Solubilidad , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/farmacologíaRESUMEN
New analogs of ursodeoxycholic acid and 7-epicholic acid containing a 6 alpha-methyl group were synthesized, and their physico-chemical properties were studied and compared with those of their natural analogs. The 6 alpha-methyl group slightly increases the lipophilicity and slightly lowers the critical micellar concentration with respect to the corresponding natural analogs. Simulated bile 50% enriched with 6 alpha-methyl ursodeoxycholic acid, with a total bile acid/phospholipid ratio of 10/1, demonstrated a higher cholesterol-holding capacity and a faster cholesterol gallstone dissolution rate with respect to ursodeoxycholic acid, while 6 alpha-methyl-7-epicholic acid and 7-epicholic acid were much less efficient in these processes. The 6 alpha-methyl analogs were highly stable toward 7-dehydroxylation when incubated with human stool in anaerobic conditions. Their transport, metabolism, and effect on biliary lipid secretion were evaluated both in rats and hamsters after acute intravenous and intraduodenal infusion at a dose of 10 mumol/min per kg. In both species, 6 alpha-methyl ursodeoxycholic acid is efficiently secreted in bile, with a cumulative recovery similar to that of ursodeoxycholic acid. The only metabolites of 6 alpha-methyl ursodeoxycholic acid identified were its glycine and taurine amidated forms. 6 alpha-Methyl-7-epicholic acid was efficiently secreted into bile when infused intravenously, and to a lesser extent when infused intraduodenally, in both rats and hamsters; it was secreted in bile as amidate and also as free acid. When 6 alpha-methyl ursodeoxycholic acid, 6 alpha-methyl-7-epicholic acid, ursodeoxycholic acid, and 7-epicholic acid were chronically administered to hamsters (for 3 weeks, at a dose of 50 mg/kg per day) their accumulation in gallbladder bile was, respectively, 25.1%, 4.0%, 15.2%, and 3.4% of the total bile acids. In conclusion, of the two analogs, only 6 alpha-methyl ursodeoxycholic acid shows potential as a cholesterol gallstone-dissolving agent. In this regard, its most important properties are moderate lipophilicity, good metabolic stability, and better conservation in the enterohepatic circulation, with respect to ursodeoxycholic acid.
Asunto(s)
Ácidos y Sales Biliares/química , Ácidos Cólicos/química , Ácido Ursodesoxicólico/análogos & derivados , Animales , Bilis/metabolismo , Fenómenos Químicos , Química Física , Colesterol/metabolismo , Ácidos Cólicos/metabolismo , Ácidos Cólicos/farmacocinética , Cricetinae , Hidroxilación , Hígado/metabolismo , Masculino , Mesocricetus , Fosfolípidos/metabolismo , Ratas , Ratas Sprague-Dawley , Ácido Ursodesoxicólico/química , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/farmacocinéticaRESUMEN
The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitrobenzoyl)alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydroxylase are reported. The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM as an inhibitor of kynureninase. When administered to rats, m-NBA significantly increases the concentration of kynurenine and kynurenic acid in the brain as well as in blood and in the liver. m-NBA has also been shown to increase the concentration of kynurenic acid in hippocampal extracellular fluid. This increase is associated with sedative and anticonvulsant activities, thus confirming the possibility of antagonizing L-glutamate-mediated effects by modulating the kynurenine pathway of L-tryptophan metabolism.
Asunto(s)
Alanina/análogos & derivados , Quinurenina/análogos & derivados , Oxigenasas de Función Mixta/antagonistas & inhibidores , Alanina/síntesis química , Alanina/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Unión Competitiva , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hidrolasas/antagonistas & inhibidores , Ácido Quinurénico/sangre , Ácido Quinurénico/metabolismo , Quinurenina/sangre , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa , Hígado/efectos de los fármacos , Hígado/metabolismo , Modelos Moleculares , Estructura Molecular , Actividad Motora/efectos de los fármacos , Ratas , Convulsiones/tratamiento farmacológico , Triptófano/metabolismoRESUMEN
3 alpha,7 beta-Dihydroxy-23-methyl-5 beta-cholan-24-oic acid (MUDCA) and its two diastereoisomers, alpha- and beta-MUDCA, were infused intraduodenally in biliary fistula hamsters in order to evaluate the effect on bile flow and their hepatic biotransformation processes compared with the natural analog ursodeoxycholic acid (UDCA). In addition, the corresponding glycine conjugates were compared. The bile acids were administered at different doses (0.7-6 mumol/min/kg) over periods of 90 min. The results indicate that the racemic mixture exhibits a potent choleretic effect at both low and high doses, while the two individual diastereoisomers show this effect only at high doses. The presence of a C-23 methyl group in the side chain prevents hepatic amidation and alternative conjugations occur, such as glucuronidation, in order to facilitate their biliary secretion. Biotransformation of the methyl derivatives of UDCA occurred mainly by conversion to more polar glucuronide conjugates. There was little alteration to the molecule and, unlike UDCA, very little amidation occurred. These data indicate that the presence of a C-23 methyl group prevents the usual side-chain amidation common to the most naturally occurring bile acids and that glucuronidation is a requisite for efficient biliary excretion.
Asunto(s)
Bilis/efectos de los fármacos , Ácido Ursodesoxicólico/análogos & derivados , Enfermedad Aguda , Animales , Bicarbonatos/metabolismo , Bilis/química , Bilis/metabolismo , Fístula Biliar/metabolismo , Biotransformación , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Duodeno , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Mesocricetus , Estereoisomerismo , Relación Estructura-Actividad , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/análisis , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/farmacologíaRESUMEN
The four D-2-amino-4,5-methano-adipates 26, 27, 32, 33 were synthesized and their biological activity at the N-methyl-D-aspartate (NMDA) receptor was assessed. The synthesis involved as a key step a rhodium acetate dimer catalyzed addition of ethyl diazoacetate to the protected D-allylglycine (17). In vitro receptor binding using L-[3H]glutamate as the radioligand provided affinity data, while modulation of [3H]TCP binding was used as a functional assay. The analogues were also evaluated in [3H]kainate and [3H]AMPA binding to assess selectivity over non-NMDA glutamate receptors. Three of the four diastereoisomer, D-CAA B (27), C (32) and D (33) were shown to have agonist properties at the NMDA-site, while the fourth, (2R,4R,5R) D-CAA A (26) was characterized as an NMDA-site atypic antagonist.