Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Xenobiotica ; 42(10): 980-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22540538

RESUMO

1. As intestinal glucuronidation has been suggested to generate the low oral bioavailability (F) of drugs, estimating its effects would be valuable for selecting drug candidates. Here, we investigated the absorption and intestinal availability (F(a)F(g)) in animals, and intrinsic clearance via UDP-glucuronosyltransferase (UGT) in intestinal microsomes (CL(int,UGT)) for three drug candidates possessing a carboxylic acid group, in an attempt to estimate the impact of intestinal glucuronidation on F and select potential drug candidates with high F in humans. 2. The F(a)F(g) values of the three test compounds were low in rats and monkeys (0.16-0.51), and high in dogs (≥0.81). Correspondingly, the CL(int,UGT) values were high in rats and monkeys (101-731 µL/min/mg), and low in dogs (≤ 59.6 µL/min/mg). A good inverse correlation was observed between F(a)F(g) and CL(int,UGT), suggesting that intestinal glucuronidation was a major factor influencing F(a)F(g) of these compounds. 3. By applying this correlation to F(a)F(g) in humans using human CL(int,UGT) values (26.9-114 µL/min/mg), compounds 1-3 were predicted to have relatively high F(a)F(g). 4. Our approach is expected to be useful for estimating the impact of intestinal glucuronidation on F in animals and semiquantitatively predicting human F for drug candidates.


Assuntos
Bioquímica/métodos , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Mucosa Intestinal/metabolismo , Administração Intravenosa , Administração Oral , Animais , Cães , Glucuronídeos/administração & dosagem , Glucuronídeos/química , Glucuronídeos/farmacocinética , Haplorrinos , Humanos , Isoenzimas/metabolismo , Masculino , Membranas Artificiais , Metaboloma , Microssomos/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Padrões de Referência , Especificidade por Substrato
2.
Xenobiotica ; 41(5): 372-84, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21385103

RESUMO

We describe the preclinical and clinical pharmacokinetic profiles of FK3453 [6-(2-amino-4-phenylpyrimidin-5-yl)-2-isopropylpyridazin-3(2H)-one] and the mechanism responsible for poor oral exposure of FK3453 in humans. FK3453 showed favourable profiles in preclinical pharmacokinetic studies, including satisfactory absolute bioavailability and total body clearance in animals (30.5%-41.4%, 54.7%-68.2%, and 71.3%-93.4% and 10.8-17.6, 1.9-17.1, and 5.0 mL/min/kg in male rats, female rats, and dogs, respectively), and good metabolic stability in liver microsomes (42.3, 14.5, and 1.1 mL/min/kg in male rats, dogs, and humans, respectively). However, despite these promising preclinical findings, plasma concentrations of FK3453 in humans were extremely low, with the oxidative metabolite of the aminopyrimidine moiety (M4) identified as a major metabolite. Given that aldehyde oxidase (AO) and xanthine oxidase (XO) were presumed to be the enzymes responsible for M4 formation, we investigated the mechanism of M4 formation using human liver subcellular fractions. M4 was detected in the incubation mixture with S9 and cytosol but not with microsomes, and M4 formation was inhibited by AO inhibitors (menadione, isovanillin) but not by cytochrome P-450 inhibitor (1-aminobenzotiazole) or XO inhibitor (allopurinol). These results suggest M4 formation is catalyzed by AO, and therefore, its poor exposure in humans was attributed to extensive AO metabolism.


Assuntos
Aldeído Oxidase/metabolismo , Metaboloma , Piridazinas/metabolismo , Piridazinas/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Administração Oral , Adulto , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Citosol/enzimologia , Cães , Feminino , Humanos , Injeções Intravenosas , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas , Ligação Proteica , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/metabolismo , Fatores de Tempo , Adulto Jovem
3.
Drug Metab Pharmacokinet ; 25(3): 223-35, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20610881

RESUMO

The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.


Assuntos
Hepatócitos/metabolismo , Fígado/metabolismo , Desintoxicação Metabólica Fase II , Preparações Farmacêuticas/metabolismo , Quimeras de Transplante/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/metabolismo , Debrisoquina/metabolismo , Regulamentação Governamental , Hepatócitos/citologia , Hepatócitos/transplante , Humanos , Fígado/citologia , Fígado/enzimologia , Desintoxicação Metabólica Fase I , Camundongos , Modelos Animais , Ratos , Varfarina/metabolismo
4.
J Med Chem ; 48(15): 4750-3, 2005 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-16033254

RESUMO

From metabolic considerations and prediction of an inhibitor-induced conformational change, novel adenosine deaminase (ADA) inhibitors with improved activities and oral bioavailability have been developed on the basis of our originally designed non-nucleoside ADA inhibitors. They demonstrated in vivo efficacy in models of inflammation and lymphoma. Furthermore, X-ray crystal structure analysis has revealed a novel induced fit to ADA.


Assuntos
Inibidores de Adenosina Desaminase , Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Benzoxazóis/síntese química , Imidazóis/síntese química , Adenosina Desaminase/química , Adenosina Desaminase/metabolismo , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Desenho de Fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Camundongos , Camundongos SCID , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Proteica , Ratos , Relação Estrutura-Atividade , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Chem ; 47(15): 3730-43, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15239652

RESUMO

We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide 8c.


Assuntos
Inibidores de Adenosina Desaminase , Amidas/síntese química , Imidazóis/síntese química , Indóis/síntese química , Adenosina Desaminase/química , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Indóis/química , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ureia/química
6.
J Med Chem ; 47(11): 2728-31, 2004 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-15139750

RESUMO

We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered two inhibitors with improved oral bioavailability [6 (K(i) = 13 nM, BA = 44%) and 7 (K(i) = 9.8 nM, BA = 42%)]. 6 demonstrated in vivo efficacy in models of inflammation and lymphoma.


Assuntos
Inibidores de Adenosina Desaminase , Imidazóis/síntese química , Naftalenos/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Desenho de Fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacologia , Ratos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...