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1.
J Med Chem ; 60(12): 4932-4948, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28537398

RESUMO

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Actinas/antagonistas & inibidores , Adamantano/administração & dosagem , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/química , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Meia-Vida , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Obesos , Ratos , Relação Estrutura-Atividade
2.
J Med Chem ; 60(12): 5193-5208, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
3.
Bioanalysis ; 8(15): 1611-1622, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27397670

RESUMO

BACKGROUND: Isomerization of aspartic acid and deamidation of asparagine are two common amino acid modifications that are of particular concern if located within the complementarity-determining region of therapeutic antibodies. Questions arise as to the extent of modification occurring in circulation due to potential exposure of the therapeutic antibody to different pH regimes. RESULTS: To enable evaluation of site-specific isomerization and deamidation of human mAbs in vivo, immunoprecipitation (IP) has been combined with LC-MS providing selective enrichment, separation and detection of naive and modified forms of tryptic peptides comprising complementarity-determining region sequences. CONCLUSION: IP-LC-MS can be applied to simultaneously quantify in vivo drug concentrations and measure the extent of isomerization or deamidation in PK studies conducted during the drug discovery stage.


Assuntos
Anticorpos Monoclonais/química , Asparagina/análise , Ácido Aspártico/análise , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/sangue , Cromatografia Líquida/métodos , Humanos , Imunoprecipitação/métodos , Isomerismo , Macaca fascicularis , Masculino , Espectrometria de Massas em Tandem/métodos
4.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683

RESUMO

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

5.
Bioanalysis ; 6(13): 1795-811, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25157486

RESUMO

BACKGROUND: The disease state can modulate the penetration of large antibody-sized therapeutic molecules into affected tissues. Suitable bioanalytical methods are required for the quantitative analysis of drug tissue levels to enable a better understanding of the parameters influencing drug penetration and target engagement. RESULTS: Described is a sensitive and selective LC-MS/MS assay for the quantification of human mAb molecules in mouse tissues. By homogenizing tissues directly into serum, a common serum calibration curve can be used for multiple tissues. A generic procedure was used for affinity enrichment. An analytical range of 20 - 20,000 ng/ml was achieved in serum. CONCLUSION: The method described here can be applied for the quantitative analysis of mAb and Fc-fusion therapeutic molecules in a variety of animal tissue matrices.


Assuntos
Anticorpos Monoclonais/análise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados/análise , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/metabolismo , Cromatografia de Afinidade , Feminino , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Peptídeos/análise , Análise de Regressão , Pele/metabolismo , Tripsina/metabolismo , Ustekinumab
6.
Bioorg Med Chem Lett ; 24(2): 654-60, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24360604

RESUMO

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Tetrazóis/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/farmacologia , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Tetrazóis/farmacologia
7.
Bioanalysis ; 4(1): 17-28, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22191591

RESUMO

BACKGROUND: There is a need for a simple and efficient sample preparation technique for LC-MS/MS quantification of large therapeutic proteins in plasma. RESULTS: The sample preparation technique presented here is based upon trypsin digestion of the pellet obtained following precipitation of the protein analyte from plasma. The pellet digestion technique was shown to facilitate efficient digestion of large therapeutic proteins, with concomitant removal of a substantial amount of potentially problematic plasma phospholipids. The technique was successfully applied to a pharmacokinetic study of a large therapeutic protein. CONCLUSION: This simple sample preparation approach will be beneficial to bioanalytical laboratories engaged in the LC-MS/MS quantification of large therapeutic proteins in biological matrices.


Assuntos
Proteínas Sanguíneas/análise , Cromatografia Líquida/métodos , Manejo de Espécimes/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Proteínas Sanguíneas/química , Proteólise
8.
Bioanalysis ; 4(1): 29-40, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22191592

RESUMO

BACKGROUND: There is considerable interest in the pharmaceutical industry today in both development of therapeutic proteins as viable biopharmaceutical agents as well as the implementation of microsampling techniques, such as dried blood spots (DBS), as an alternative to current sample collection and handling procedures for biological samples generated in drug discovery and development studies. We have demonstrated that these two techniques can be integrated by developing bioanalytical methods that simultaneously determine the concentrations of unique therapeutic protein constructs, using LC-MS-based detection of multiple surrogate peptides following direct trypsin digestion of DBS. RESULTS: Bioanalytical methods were developed for the simultaneous determination of two structurally different therapeutic proteins (PEGylated-Adnectin™-1, MW 11,144 amu and an Fc-fusion protein, MW 67,082 amu) in a single DBS sample using LC-MS-based detection of multiple peptides generated from different regions of the proteins following trypsin digestion. The same methodology was applied to the analysis of DBS samples collected following dosing of a third unique protein (PEGylated-Adnectin-2) to mice. Although these initial DBS methods were slightly less sensitive than those developed specifically for each individual protein in plasma or serum, the generic digestion procedure yielded sufficient accuracy, precision and an extended linear dynamic range to justify their further evaluation in pharmacokinetic, pharmacodynamic and toxicological studies of selected therapeutic proteins following dosing in preclinical discovery studies. Additionally, DBS samples may offer a convenient, generic platform approach for direct enzymatic digestion and sample preparation for LC-MS-based quantitation of proteins. DBS samples prepared for two of the therapeutic proteins were also stable for at least 2 weeks when stored at room temperature. CONCLUSION: Although the same clarification and interpretation of DBS results will be required (e.g., blood vs plasma levels, hematocrit effects on DBS determinations and red blood cell partitioning) as for small-molecules, there still remains the potential to further develop and expand this strategy with appropriate proteins of interest. While additional studies will be required to validate this approach in specific applications, we have demonstrated the feasibility of using DBS sampling to directly quantify structurally different types of therapeutic proteins in blood in discovery studies and present the potential to simultaneously measure other proteins, such as biomarkers, to augment and integrate data generated from in vivo studies.


Assuntos
Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Peptídeos/sangue , Espectrometria de Massas em Tandem/métodos , Tripsina/química , Animais , Humanos , Camundongos , Tripsina/metabolismo
10.
Bioorg Med Chem Lett ; 21(22): 6693-8, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21983444

RESUMO

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade
11.
J Pharm Sci ; 100(7): 2979-88, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21254068

RESUMO

A preclinical canine model capable of predicting a compound's potential for pH-dependent absorption in humans was developed. This involved the surgical insertion of a gastrostomy feeding tube into the stomach of a beagle dog. The tube was sutured in position to allow frequent withdrawal of gastric fluid for pH measurement. Therefore, it was possible to measure pH in the stomach and assess the effect of gastric pH-modifying agents on the absorption of various test compounds. Fasted gastric pH in the dog showed considerable inter- and intra-animal variability. Pretreatment of pentagastrin (6 µg/kg intramuscularly) 20 min prior to test compound administration was determined to be adequate for simulating fasting stomach pH in humans. Pretreatment with famotidine [40 mg orally] 1 h prior to test compound administration was determined to be adequate for simulating human gastric pH when acid-reducing agents are coadministered. Pentagastrin and famotidine pretreatments were used to test two discovery compounds and distinct differences in their potential for pH-dependent absorption were observed. The model described herein can be used preclinically to screen out compounds, differentiate compounds, and support the assessment of various formulation- and prodrug-based strategies to mitigate the pH effect.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Suco Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Absorção Intestinal , Modelos Animais , Preparações Farmacêuticas/metabolismo , Farmacocinética , Administração Oral , Animais , Gorduras na Dieta/administração & dosagem , Cães , Famotidina/administração & dosagem , Jejum/metabolismo , Gastrostomia/instrumentação , Concentração de Íons de Hidrogênio , Injeções Intramusculares , Absorção Intestinal/efeitos dos fármacos , Masculino , Pentagastrina/administração & dosagem , Estômago/efeitos dos fármacos , Fatores de Tempo
12.
J Pharm Sci ; 99(8): 3579-93, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20166197

RESUMO

BMS-690514, a potent inhibitor of human epidermal growth factor receptor (HER) 1 (EGFR), 2, and 4, and vascular endothelial growth factor receptors (VEGFR) 1-3, is currently under investigation as an oral agent for the treatment of solid tumors. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism. Through integration of in vitro and in vivo pharmacokinetic data and antitumor efficacy in nude mice, human pharmacokinetics and efficacious doses were projected for BMS-690514. The oral bioavailability of BMS-690514 was 78% in mice, approximately 100% in rats, 8% in monkeys, and 29% in dogs. The low oral bioavailability in monkeys could be attributed to high systemic clearance in that species, which was also consistent with predicted clearance using in vitro data from monkey liver microsomes. Permeability of BMS-690514 in Caco-2 cells was in the intermediate range with a moderate potential to be a P-gp substrate. Experiments using recombinant human CYP enzymes and human liver microsomes suggested that CYP2D6 and CYP3A4 are likely to play a key role in the metabolic clearance of BMS-690514; in addition, direct glucuronidation of BMS-690514 was also observed in human hepatocytes. BMS-690514 was able to cross the blood-brain barrier with a brain-to-plasma ratio of approximately 1. The preclinical ADME properties of BMS-690514 suggest good oral bioavailability in humans and metabolism by multiple pathways including oxidation and glucuronidation. Based on the efficacious AUC in nude mice and predicted human pharmacokinetics, the human efficacious QD dose is predicted to be in the range of 100-200 mg.


Assuntos
Receptores ErbB/antagonistas & inibidores , Piperidinas/farmacocinética , Pirróis/farmacocinética , Triazinas/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Algoritmos , Animais , Proteínas Sanguíneas/química , Química Encefálica , Células CACO-2 , Permeabilidade da Membrana Celular , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Cães , Excipientes , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/metabolismo , Permeabilidade , Piperidinas/análise , Ligação Proteica , Pirróis/análise , Ratos , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta , Espectrometria de Massas em Tandem , Triazinas/análise
13.
J Pharm Sci ; 99(7): 3234-45, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20112434

RESUMO

Identification and quantitation of drug metabolites are important for understanding and predicting drug-drug interactions and toxicities. For chiral compounds, metabolic interconversion of enantiomers may present unique challenges. If the stereoisomers are biologically distinguishable, regulatory agencies consider them distinct chemical entities and require individual characterization since enantiomers may exhibit different pharmacokinetic, pharmacologic, and toxicologic properties. Efforts to predict enantiomeric ratios in humans from animal studies are frequently hampered by a lack of understanding of the enzymes responsible and potential interspecies differences. In this study, liver microsomes from rats, dogs, and monkeys were used to investigate the kinetics of interconversion of two enantiomeric secondary alcohols (Compounds A and C) via oxidation to a ketone intermediate (Compound B) and subsequent reduction of the ketone to either regenerate the starting alcohol, or produce the enantiomer. A mechanistic model was established using in vitro microsomal data to predict the ratios of the enantiomer concentrations in plasma 24 hours after dosing and the ratios of AUC values for the enantiomers. Plasma concentrations of the enantiomers and ketone intermediate were determined after single intravenous and oral doses of Compound C. The observed concentration and AUC ratios were similar to the values predicted by the mechanistic model.


Assuntos
Álcoois/metabolismo , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Álcoois/química , Álcoois/farmacocinética , Animais , Cães , Haplorrinos , Cinética , Masculino , Modelos Biológicos , Oxirredução , Preparações Farmacêuticas/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 17(17): 4947-54, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17606372

RESUMO

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.


Assuntos
Química Farmacêutica/métodos , Receptores ErbB/química , Neoplasias/tratamento farmacológico , Piperidinas/síntese química , Pirróis/síntese química , Receptor ErbB-2/química , Triazinas/síntese química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Insetos , Modelos Químicos , Transplante de Neoplasias , Piperidinas/química , Piperidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Triazinas/química , Triazinas/farmacologia
15.
Bioorg Med Chem Lett ; 17(14): 4006-11, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17502137

RESUMO

We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.


Assuntos
Alanina/análogos & derivados , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzodiazepinonas/farmacologia , Inibidores Enzimáticos/farmacologia , Alanina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Animais , Camundongos , Camundongos Transgênicos , Modelos Moleculares
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