RESUMO
Novel fatty acid-bile acid conjugates (1a-1k) were designed and synthesized by coupling of the fatty acids to the 3-OH of bile acids using lysine for linkage. In the conjugates, the 24-COOH of the bile acids was kept intact to preserve liver-specific recognition. The ability of the newly synthesized conjugates (at 100 mg/kg dosage) to reduce total cholesterol (TC) and triglyceride (TG) levels in mice fed with high-fat diet (HFD) was evaluated. Conjugates of stearic acid with cholic acid and palmitic acid with ursodeoxycholic acid (at dosages of 50, 100, and 200 mg/kg) were further evaluated to determine their ability to reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), TC, and TG levels in mice fed with HFD. All conjugates showed potent hypolipidemic activity. Further investigation revealed that compounds 1c and 1 g not only dose-dependently reduced serum levels of TC and TG, but also inhibited the elevation of serum AST and ALT levels in mice fed with HFD. Thus, compounds 1c and 1 g are promising hypolipidemic agents with hepatocyte protective effects against HFD-induced liver damage.
Assuntos
Ácidos e Sais Biliares/administração & dosagem , Ácidos Graxos/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/química , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/química , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/patologia , Hipolipemiantes/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Lisina/química , Camundongos , Triglicerídeos/sangueRESUMO
Three series of apigenin derivatives have been prepared by coupling the carboxyl alkyl group to 4'-, 5- or 7-hydroxyl groups of apigenin respectively. Preliminary biological evaluation in vitro revealed that xanthine oxidase inhibitory activity was improved by modifications at 4'-position and decreased by similar modifications at 5-, 7-positions while α-glucosidase inhibitory activity was maintained by modifications at 5-, 7-positions but lost by modifications at 4'-position. Administration (ip) of 7e markedly lowered serum uric acid levels in potassium oxonate induced hyperuricemic mouse model and administration (p.o.) of 11d or 11e effectively suppressed the elevation of serum glucose in the oral sucrose tolerance test in mice, while apigenin were not significantly effective in both tests.
Assuntos
Apigenina/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Xantina Oxidase/antagonistas & inibidores , alfa-Glucosidases/química , Animais , Apigenina/metabolismo , Apigenina/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Flavonoides/química , Teste de Tolerância a Glucose , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Infusões Parenterais , Camundongos , Ligação Proteica , Relação Estrutura-Atividade , Ácido Úrico/sangue , Xantina Oxidase/metabolismo , alfa-Glucosidases/metabolismoRESUMO
Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of-flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Sufficient enzymatic activation in the liver homogenate through a relatively simple metabolic pathway, in addition to a favorable stability profile in rat plasma, made Chemical II an optimal candidate. Next, six analogues based on the structure of Chemical II were synthesized and evaluated in plasma and liver homogenate. Compared to Chemical II, these compounds generated less active PMEA levels in rat liver homogenate. Therefore, chemical modification of Chemical II may lead to new promising PMEA derivatives with enhanced plasma stability and liver activation.
Assuntos
Adenina/análogos & derivados , Antivirais/sangue , Antivirais/síntese química , Vírus da Hepatite B/efeitos dos fármacos , Fígado/efeitos dos fármacos , Organofosfonatos/sangue , Organofosfonatos/síntese química , Adenina/sangue , Adenina/síntese química , Adenina/farmacologia , Animais , Antivirais/farmacologia , Biotransformação , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ésteres , Técnicas In Vitro , Fígado/metabolismo , Estrutura Molecular , Organofosfonatos/farmacologia , Ratos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Depression is a severe mood disorder with increasing morbidity and suicidality, while the current therapy is not satisfactory. Serotonin and noradrenaline reuptake inhibitors (SNRIs) have been reported to have higher efficacy and/or faster acting rate than commonly used antidepressants. The present study was designed to screen the potential SNRIs, using in vitro radioligand receptor binding assays and in vivo animal tests, and introduced the discovery of 071031B. In the tail suspension test and forced swimming test in mice, six compounds (071017S, 071026W, 071031A, 071031B, 080307A and 080307B) showed robust antidepressant activity, without stimulant effect on the locomotor activity or other side effects, and the minimal effective dose of 071017S, 071026W, 071031A and 071031B was less than that of duloxetine; in vitro binding tests indicated that 071031B had high affinity to both serotonin transporter and noradrenaline transporter with similar inhibitory rates to duloxetine at 1 and 100 nM; acute toxicity test indicated that the LD50 value of 071031B was similar to that of duloxetine. These findings demonstrated that this integrated system, combining high throughput screening technology and in vivo animal tests, is effective to screen potential monoamine reuptake inhibitors fast and accurately; 071031B is expected to be a novel serotonin and noradrenaline reuptake inhibitor for its robust antidepressant activity and transporter affinity.