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1.
Bioorg Med Chem Lett ; 27(6): 1360-1363, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28223020

RESUMO

A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.


Assuntos
Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Disponibilidade Biológica , Pró-Fármacos/farmacocinética , Pirazinas/farmacocinética , Ratos
2.
J Pharmacol Exp Ther ; 358(3): 371-86, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27411717

RESUMO

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.


Assuntos
Neuralgia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Medula Espinal/fisiopatologia
3.
Bioorg Med Chem Lett ; 26(9): 2184-7, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27020524

RESUMO

A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.


Assuntos
Carbamatos/farmacologia , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/metabolismo , Linhagem Celular Tumoral , Humanos , Microssomos Hepáticos/metabolismo , Pirazinas/síntese química , Pirazinas/metabolismo , Ratos , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 25(22): 5040-7, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26497283

RESUMO

The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Guanidinas/farmacologia , Compostos Macrocíclicos/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/biossíntese , Animais , Células CACO-2 , Catepsina D/antagonistas & inibidores , Catepsina E/antagonistas & inibidores , Cães , Guanidinas/síntese química , Humanos , Compostos Macrocíclicos/síntese química , Células Madin Darby de Rim Canino , Masculino , Camundongos , Simulação de Acoplamento Molecular , Pepsina A/antagonistas & inibidores , Prolina/síntese química , Inibidores de Proteases/síntese química
6.
J Neurosci ; 35(17): 6931-6, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25926467

RESUMO

Multiple small-molecule inhibitors of the ß-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid ß (Aß) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3-23.5 µg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2-13 µm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Aß levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ∼1 µg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/patologia , Transtornos Cognitivos/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Microglia/efeitos dos fármacos , Fatores Etários , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Humanos , Infusões Intraventriculares , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/patologia , Mutação/genética , Neurônios/efeitos dos fármacos , Neurônios/patologia
7.
Int J Alzheimers Dis ; 2014: 431858, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25097793

RESUMO

Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-ß peptide (Aß), particularly the 42-amino acid Aß1-42, in the brain. Aß1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aß production. BMS-869780 is a potent GSM that decreased Aß1-42 and Aß1-40 and increased Aß1-37 and Aß1-38, without inhibiting overall levels of Aß peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aß1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aß1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aß1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aß1-42 without Notch-related side effects.

9.
Bioanalysis ; 4(15): 1895-905, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22943620

RESUMO

BACKGROUND: The polar nucleoside drug ribavirin (RBV) combined with IFN-α is a front-line treatment for chronic hepatitis C virus infection. RBV acts as a prodrug and exerts its broad antiviral activity primarily through its active phosphorylated metabolite ribavirin 5´-triphosphate (RTP), and also possibly through ribavirin 5´-monophosphate (RMP). To study RBV transport, diffusion, metabolic clearance and its impact on drug-metabolizing enzymes, a LC-MS method is needed to simultaneously quantify RBV and its phosphorylated metabolites (RTP, ribavirin 5´-diphosphate and RMP). In a recombinant human UGT1A1 assay, the assay buffer components uridine and its phosphorylated derivatives are isobaric with RBV and its phosphorylated metabolites, leading to significant interference when analyzed by LC-MS with the nominal mass resolution mode. RESULTS: Presented here is a LC-MS method employing LC coupled with full-scan high-resolution accurate MS analysis for the simultaneous quantitative determination of RBV, RMP, ribavirin 5´-diphosphate and RTP by differentiating RBV and its phosphorylated metabolites from uridine and its phosphorylated derivatives by accurate mass, thus avoiding interference. CONCLUSION: The developed LC-high-resolution accurate MS method allows for quantitation of RBV and its phosphorylated metabolites, eliminating the interferences from uridine and its phosphorylated derivatives in recombinant human UGT1A1 assays.


Assuntos
Antivirais/análise , Antivirais/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Ribavirina/análise , Ribavirina/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Monofosfato de Adenosina , Cromatografia por Troca Iônica/métodos , Glucuronosiltransferase/análise , Glucuronosiltransferase/metabolismo , Hepatite C Crônica/tratamento farmacológico , Humanos , Nucleotídeos/análise , Ribavirina/análogos & derivados , Uridina/análise , Difosfato de Uridina/análise , Uridina Monofosfato/análise
10.
Bioorg Med Chem Lett ; 21(22): 6909-15, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21974952
11.
Eur J Drug Metab Pharmacokinet ; 36(3): 129-39, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21461793

RESUMO

Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST(®) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC(50) values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 µM for rat and dog, respectively. The apparent K ( i ) values for PT were approximately 1.7, 6.6, and 4.8 µM for rat, dog and chimpanzee, respectively. The apparent K ( i ) for HCT was approximately 1.3 µM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.


Assuntos
Anticoagulantes/farmacocinética , Inibidores do Fator Xa , Pirazóis/farmacocinética , Piridonas/farmacocinética , Animais , Proteínas Sanguíneas/metabolismo , Cães , Humanos , Taxa de Depuração Metabólica , Pan troglodytes , Ligação Proteica , Pirazóis/farmacologia , Piridonas/farmacologia , Ratos , Especificidade da Espécie , Tempo de Coagulação do Sangue Total
12.
Bioorg Med Chem Lett ; 21(1): 537-41, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21078556

RESUMO

Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aß levels, but did not lower rat brain Aß due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.


Assuntos
Aminas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Indóis/síntese química , Inibidores de Proteases/química , Piridinas/síntese química , Aminas/síntese química , Aminas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Indóis/química , Indóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade
13.
Drug Metab Dispos ; 38(1): 16-24, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19833845

RESUMO

Monkeys have been proposed as an animal model to predict the magnitude of human clinical drug-drug interactions caused by CYP3A4 enzyme induction. To evaluate whether the cynomolgus monkey can be an effective in vivo model, human CYP3A4 inducers were evaluated both in vitro and in vivo. First, a full-length pregnane X receptor (PXR) was cloned from the cynomolgus monkey, and the sequence was compared with those of rhesus monkey and human PXR. Cynomolgus and rhesus monkey PXR differed by only one amino acid (A68V), and both were highly homologous to human PXR (approximately 96%). When the transactivation profiles of 30 compounds, including known inducers of CYP3A4, were compared between cynomolgus and human PXR, a high degree of correlation with EC(50) values was observed. These results suggest that cynomolgus and human PXR respond in a similar fashion to these ligands. Second, two known human CYP3A4 inducers, rifampicin and hyperforin, were tested in monkey and human primary hepatocytes for induction of CYP3A enzymes. Both monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A8 and CYP3A4, respectively. Lastly, in vivo induction of CYP3A8 by rifampicin and hyperforin was shown by significant reductions of midazolam exposure that were comparable with those in humans. These results show that the cynomolgus monkey can be a predictive in vivo animal model of PXR-mediated induction of human CYP3A4 and can provide a useful assessment of the resulting pharmacokinetic changes of affected drugs.


Assuntos
Citocromo P-450 CYP3A/biossíntese , Hepatócitos/metabolismo , Macaca fascicularis , Receptores de Esteroides/metabolismo , Xenobióticos/farmacocinética , Adulto , Sequência de Aminoácidos , Animais , Compostos Bicíclicos com Pontes/sangue , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clonagem Molecular , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos/genética , Indução Enzimática/efeitos dos fármacos , Indução Enzimática/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hypericum/química , Macaca mulatta , Masculino , Midazolam/sangue , Midazolam/metabolismo , Midazolam/farmacocinética , Pessoa de Meia-Idade , Modelos Animais , Dados de Sequência Molecular , Floroglucinol/análogos & derivados , Floroglucinol/sangue , Floroglucinol/farmacocinética , Floroglucinol/farmacologia , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Receptor de Pregnano X , Receptores de Esteroides/genética , Rifampina/sangue , Rifampina/farmacocinética , Rifampina/farmacologia , Homologia de Sequência de Aminoácidos , Terpenos/sangue , Terpenos/farmacocinética , Terpenos/farmacologia , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Transfecção
14.
J Med Chem ; 52(23): 7653-68, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19954247

RESUMO

Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.


Assuntos
Pirazinas/metabolismo , Pirazinas/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Masculino , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos
15.
J Med Chem ; 52(14): 4161-72, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19552436

RESUMO

A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.


Assuntos
Pirazinas/farmacologia , Pirazinas/farmacocinética , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Humanos , Concentração Inibidora 50 , Masculino , Taxa de Depuração Metabólica , Pirazinas/química , Pirazinas/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo
16.
J Med Chem ; 52(14): 4173-91, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19552437

RESUMO

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.


Assuntos
Pirazinas/química , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Macaca fascicularis , Masculino , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
17.
J Pharmacol Exp Ther ; 326(2): 502-13, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18499745

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo , Inibidores Enzimáticos/farmacologia , Fragmentos de Peptídeos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Secretases da Proteína Precursora do Amiloide/fisiologia , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/fisiologia , Western Blotting , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Linhagem Celular , Permeabilidade da Membrana Celular , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Fragmentos de Peptídeos/sangue , Ligação Proteica , Especificidade por Substrato
18.
J Pharm Sci ; 97(7): 2568-80, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17914718

RESUMO

N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug-drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug-drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p < 0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r = 0.97, p < 0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CL(int) estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug-drug interactions that result in confounding PK estimates do not occur as frequently as expected.


Assuntos
Inibidores do Citocromo P-450 CYP3A , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Microssomos Hepáticos , Preparações Farmacêuticas/administração & dosagem , Farmacocinética , Animais , Disponibilidade Biológica , Citocromo P-450 CYP3A , Cães , Interações de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Pan troglodytes , Ratos
19.
Drug Metab Dispos ; 35(8): 1387-92, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17494642

RESUMO

The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.


Assuntos
Buspirona/análogos & derivados , Buspirona/farmacocinética , Receptor 5-HT1A de Serotonina/metabolismo , Animais , Área Sob a Curva , Autorradiografia , Disponibilidade Biológica , Buspirona/sangue , Buspirona/metabolismo , Buspirona/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Estrutura Molecular , Piperazinas/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Ligação Proteica/efeitos dos fármacos , Piridinas/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Trítio
20.
J Pharm Sci ; 96(2): 459-72, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17075867

RESUMO

A preclinical canine model capable of predicting a compound's potential for a human food effect was developed. The beagle dog was chosen as the in vivo model. A validation set of compounds with known propensities for human food effect was studied. Several diets were considered including high-fat dog food and various quantities of the human FDA meal. The effect of pentagastrin pretreatment was also investigated. The high-fat dog food did not predict human food effect and was discontinued from further evaluation. The amount of FDA meal in the dog was important in the overall prediction of the magnitude of human food effect. Fed/fasted Cmax and AUC ratios using a 50-g aliquot of the FDA meal in the dog were in the closest qualitative agreement to human data. Pentagastrin pretreatment did not affect the AUC in the fed state, but increased the fasted AUC for weakly basic compounds. Pentagastrin pretreatment and a 50-g aliquot of the FDA meal in the dog predicted the human food effect for a validation set of compounds. This model, which is intended for compound screening, will be helpful for determining food effect as a liability when compounds progress from discovery to clinical development.


Assuntos
Gorduras na Dieta , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Alimento-Droga , Modelos Animais , Pentagastrina/farmacologia , Animais , Sulfato de Atazanavir , Disponibilidade Biológica , Cães , Inibidores da Protease de HIV/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Oligopeptídeos/farmacocinética , Pravastatina/farmacocinética , Piridinas/farmacocinética
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