RESUMO
The absorption and disposition of the serotonin 5-HT(4) receptor agonist, naronapride (6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2,2,2]oct-(R)-3-yl ester dihydrochloride; ATI-7505), were evaluated in healthy males given a single 120-mg oral dose of (14)C-labeled compound. Serial blood samples and complete urine and feces were collected up to 552 h postdose. Naronapride was extensively metabolized, undergoing rapid hydrolysis to 6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid (ATI-7500) with stoichiometric loss of quinuclidinol. ATI-7500 was either N-glucuronidated on the phenyl ring or its hexanoic acid side chain underwent two-carbon cleavage, probably through a ß-oxidation metabolic pathway, to form 4-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butanoic acid (ATI-7400). ATI-7400 underwent further side-chain oxidation to form 2-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-acetic acid (ATI-7100). Quinuclidinol, ATI-7500, ATI-7400, and ATI-7100 were the major metabolites, with plasma area under the curve values approximately 72-, 17-, 8-, and 2.6-fold that of naronapride. Naronapride, ATI-7500, ATI-7400, and ATI-7100 accounted for 32.32, 36.56, 16.28, and 1.58%, respectively, of the dose recovered in urine and feces. ATI-7400 was the most abundant radioactive urinary metabolite (7.77%), and ATI-7500 was the most abundant metabolite in feces (35.62%). Fecal excretion was the major route of elimination. Approximately 32% of the dose was excreted unchanged in feces. Naronapride, ATI-7500, and quinuclidinol reached peak plasma levels within 1 h postdose. Peak ATI-7400 and ATI-7100 concentrations were reached within 1.7 h, suggesting rapid ATI-7500 metabolism. Naronapride plasma terminal half-life was 5.36 h, and half-lives of the major metabolites ranged from 17.69 to 33.03 h. Naronapride plasma protein binding was 30 to 40%. The mean blood/plasma radioactivity ratio indicated minimal partitioning of (14)C into red blood cells.
Assuntos
Benzamidas/farmacocinética , Quinuclidinas/farmacocinética , Receptores 5-HT4 de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacocinética , Animais , Benzamidas/uso terapêutico , Cromatografia Líquida de Alta Pressão , Humanos , Masculino , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Quinuclidinas/uso terapêutico , Ratos , Agonistas do Receptor de Serotonina/uso terapêuticoRESUMO
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
Assuntos
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Farmacorresistência Bacteriana/efeitos dos fármacos , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , Acrilatos/farmacologia , Estabilidade de Medicamentos , Isomerismo , Testes de Sensibilidade Microbiana , Fotoquímica , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
Assuntos
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Proteínas de Transporte/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Pseudomonas aeruginosa/fisiologia , Pirimidinas/química , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Ligação Proteica/fisiologia , Pseudomonas aeruginosa/química , Pirimidinas/metabolismoRESUMO
A structurally simplified macrolactone analogue of halichondrin B was identified that retains the potent cell growth inhibitory activity of the natural product in vitro.
Assuntos
Éteres Cíclicos/química , Éteres Cíclicos/farmacologia , Lactonas/química , Lactonas/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Éteres Cíclicos/síntese química , Humanos , Lactonas/síntese química , Macrolídeos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.