Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Arthritis Rheumatol ; 70(8): 1331-1342, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29534336

RESUMO

OBJECTIVE: To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity. METHODS: Genes modulated by prednisolone were identified from in vitro studies using peripheral blood mononuclear cells from normal healthy volunteers. Using the criteria of a >2-fold change relative to vehicle controls and an adjusted P value cutoff of less than 0.05, 64 up-regulated and 18 down-regulated genes were identified. A composite score of the up-regulated genes was generated using a single-sample gene set enrichment analysis algorithm. RESULTS: GC gene signature expression was significantly elevated in peripheral blood leukocytes from normal healthy volunteers following oral administration of prednisolone. Expression of the signature increased in a dose-dependent manner, peaked at 4 hours postadministration, and returned to baseline levels by 48 hours after dosing. Lower expression was detected in normal healthy volunteers who received a partial GC receptor agonist, which is consistent with the reduced transactivation potential of this compound. In cohorts of patients with systemic lupus erythematosus and patients with rheumatoid arthritis, expression of the GC signature was negatively correlated with the percentages of peripheral blood lymphocytes and positively correlated with peripheral blood neutrophil counts, which is consistent with the known biology of the GC receptor. Expression of the signature largely agreed with reported GC use in these populations, although there was significant interpatient variability within the dose cohorts. CONCLUSION: The GC gene signature identified in this study represents a pharmacodynamic marker of GC exposure.

2.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Drogas , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
3.
J Med Chem ; 58(10): 4278-90, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25905990

RESUMO

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/metabolismo , Tiadiazóis/farmacologia , Animais , Sangue/efeitos dos fármacos , Sangue/metabolismo , Técnicas de Química Sintética , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Ratos Endogâmicos Lew , Receptores de Glucocorticoides/agonistas , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacocinética , Fator de Transcrição AP-1/metabolismo
4.
Bioorg Med Chem Lett ; 24(15): 3268-73, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24980053

RESUMO

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.


Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/agonistas , Tiadiazóis/farmacologia , Ureia/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Ureia/análogos & derivados , Ureia/química
5.
Bioorg Med Chem Lett ; 23(20): 5571-4, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24011644

RESUMO

A series of heterocyclic glucocorticoid receptor (GR) modulators with 2,2-dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core are described. Structure-activity relationships suggest a combination of H-bond acceptor and a 4-fluorophenyl moiety as being important structural components contributing to the glucocorticoid receptor binding and functional activity for this series of GR modulators.


Assuntos
Amidas/química , Compostos Heterocíclicos/química , Receptores de Glucocorticoides/agonistas , Tiadiazóis/química , Tiazóis/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/metabolismo , Ligação Proteica , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 23(19): 5442-7, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23953070

RESUMO

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.


Assuntos
Amidas/química , Amidas/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/agonistas , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 23(19): 5448-51, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23916594

RESUMO

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.


Assuntos
Indazóis/síntese química , Indazóis/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacologia , Humanos , Indazóis/química , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Receptores de Glucocorticoides/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Ureia/química , Ureia/farmacologia
8.
Cell Mol Immunol ; 9(4): 341-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22522653

RESUMO

When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T-cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T-cell response. Peritoneal macrophages exhibit an immature phenotype (MHC class II(lo), B7(lo)) that reduces their efficacy as antigen-presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T-cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T-cell costimulation to recover the peritoneal T-cell response. We show that CD28 ligation failed to recover the peritoneal T-cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing monoclonal antibody (mAb) treatment, this 'cosuppression' response was due to CD28 ligation increasing the number of interferon (IFN)-γ-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T-cell costimulation biology.Cellular & Molecular Immunology advance online publication, 23 April 2012; doi:10.1038/cmi.2012.13.


Assuntos
Antígenos CD28/metabolismo , Imunossupressão , Interferon gama/metabolismo , Macrófagos Peritoneais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD28/imunologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Microambiente Celular , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/metabolismo , Agregação de Receptores/imunologia , Receptor Cross-Talk
9.
J Med Chem ; 54(20): 7318-33, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-21899328

RESUMO

Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Glucocorticoides/agonistas , Tiadiazóis/síntese química , Fosfatase Alcalina/biossíntese , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Edema/tratamento farmacológico , Glutamato-Amônia Ligase/biossíntese , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Interleucina-1beta/sangue , Masculino , Modelos Moleculares , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/sangue , Tirosina Transaminase/biossíntese
10.
J Med Chem ; 53(23): 8241-51, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21073190

RESUMO

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.


Assuntos
Amidas/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Animais , Modelos Moleculares , Ratos
11.
J Med Chem ; 53(3): 1270-80, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-20047280

RESUMO

The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.


Assuntos
Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Dexametasona/farmacologia , Selectina E/genética , Selectina E/metabolismo , Genes Reporter , Células HeLa , Humanos , Isoquinolinas/química , Pulmão/citologia , Pulmão/efeitos dos fármacos , Estrutura Molecular , Regiões Promotoras Genéticas , Relação Estrutura-Atividade , Transcrição Genética , Ativação Transcricional
12.
Bioorg Med Chem Lett ; 17(3): 679-82, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17098428

RESUMO

The design, synthesis, and SAR studies of 'core' variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 approximately 10 mg/kg).


Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/farmacologia , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Camundongos , Ovalbumina , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores CCR4 , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/patologia , Relação Estrutura-Atividade
13.
Curr Top Med Chem ; 6(13): 1335-44, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16918452

RESUMO

The chemokine receptor CCR4 is broadly expressed on cells of the immune system. It is known to play a central role in T cell migration to the thymus, and T cell maturation and education. In addition, CCR4 is known to modulate T cell migration to several sites of inflammation in the body, including the skin, and lungs. It is best known as a drug target for airway inflammation and atopic dermatitis, but cells expressing CCR4 are found in many inflammatory diseases. CCR4 small molecule antagonists have not yet reached the clinic, but at least one has been validated in an in vivo model. Here we review the current status of structurally novel CCR4 receptor antagonists.


Assuntos
Desenho de Drogas , Fatores Imunológicos , Receptores de Quimiocinas/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Estrutura Molecular , Receptores CCR4 , Receptores de Quimiocinas/imunologia , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA