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1.
Toxicol Sci ; 183(1): 93-104, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34240189

RESUMO

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development.


Assuntos
Linfoma , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Animais , Testes de Carcinogenicidade , Feminino , Hiperplasia , Linfoma/induzido quimicamente , Linfoma/genética , Masculino , Camundongos , Camundongos Transgênicos
2.
J Pharmacol Exp Ther ; 326(1): 41-50, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18434589

RESUMO

The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Proc Natl Acad Sci U S A 83:3331-3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice (Proc Natl Acad Sci U S A 102:16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC(50) value of 0.2 microM. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-alpha production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.


Assuntos
Anisóis/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Anisóis/farmacologia , Artrite Experimental/patologia , Células Cultivadas , Humanos , Masculino , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Vírus do Sarcoma Felino/efeitos dos fármacos , Vírus do Sarcoma Felino/enzimologia
3.
Drug Metab Dispos ; 31(7): 870-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12814963

RESUMO

A series of N-hydroxyformamide tumor necrosis factor-alpha converting enzyme (TACE)/matrix metalloprotease (MMP) inhibitors were evaluated for their potential to induce human cytochrome P450 3A (CYP3A). Two in vitro assays were used: 1) a cell-based reporter gene assay for activation of the pregnane X receptor (PXR), and 2) a primary "sandwich" culture of human hepatocytes. Approximately 50 TACE/MMP inhibitors were evaluated in the human PXR assay. A range of PXR activation was observed, 0 to 150% of the activation of the known human CYP3A inducer rifampicin. Three TACE/MMP inhibitors were evaluated in rat and human hepatocytes. Significantly higher PXR activation/CYP3A induction was observed in PXR/hepatocyte models, respectively, for (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide (GW3333) compared with (2R,3S)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-2-isobutyl-N-[(1S,2R)-2-methoxy-1-[(1,3-thiazol-2-ylamino)carbonyl]propyl]hexanamide (GW6495) and (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]-propyl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide (GI4023). The CYP3A induction level achieved with GW3333 at a concentration of approximately 10 microM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 microM. The extent of rodent CYP3A induction caused by GW3333 was confirmed in vivo after daily oral administration for 14 days to rats. In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A.


Assuntos
Hidrocarboneto de Aril Hidroxilases/biossíntese , Formamidas/farmacologia , Hepatócitos/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Oxirredutases N-Desmetilantes/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Amidas/administração & dosagem , Amidas/farmacocinética , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Técnicas de Cultura de Células , Citocromo P-450 CYP3A , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Dipeptídeos/farmacocinética , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática , Formamidas/química , Hepatócitos/metabolismo , Humanos , Masculino , Metaloproteinases da Matriz/administração & dosagem , Metaloproteinases da Matriz/farmacocinética , Oxirredutases N-Desmetilantes/efeitos dos fármacos , Receptor de Pregnano X , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
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