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1.
J Med Chem ; 53(4): 1774-87, 2010 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-20095622

RESUMO

In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.


Assuntos
Azepinas/síntese química , Hipolipemiantes/síntese química , Indóis/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Azepinas/farmacocinética , Azepinas/farmacologia , Disponibilidade Biológica , Linhagem Celular , LDL-Colesterol/sangue , Feminino , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Macaca mulatta , Masculino , Camundongos , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Receptores de LDL/genética , Solubilidade , Relação Estrutura-Atividade , Triglicerídeos/sangue
2.
Am J Physiol Gastrointest Liver Physiol ; 296(3): G543-52, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19136377

RESUMO

The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of bile acid, triglyceride (TG), and cholesterol homeostasis. WAY-362450 (FXR-450/XL335) is a potent synthetic FXR agonist as characterized in luciferase reporter assays and in mediating FXR target gene regulation in primary human and immortalized mouse hepatocytes. In vivo, WAY-362450 dose dependently decreased serum TG levels after 7 days of oral dosing in western diet-fed low-density lipoprotein receptor-/- mice and in the diabetic mouse strains KK-Ay and db/db comparable to that achieved with the peroxisome proliferator activated receptor-alpha agonist, fenofibrate. WAY-362450 treatment also reduced serum cholesterol levels via reductions in LDLc, VLDLc, and HDLc lipoprotein fractions that were not accompanied by hepatic cholesterol accumulation. This cholesterol lowering was dependent on FXR as demonstrated in a hypothyroid-induced hypercholesterolemia setting in FXR-/- mice. In fructose-fed models, WAY-362450 also decreased TG and VLDLc levels in rats and hamsters but significantly increased HDLc levels in rats while reducing HDLc levels in hamsters. The differential effect of WAY-362450 on HDLc is likely due to a murine-specific induction of endothelial lipase and scavenger receptor-BI that does not occur in rats. These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia.


Assuntos
Azepinas/farmacologia , Colesterol/sangue , Proteínas de Ligação a DNA/agonistas , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Indóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , Azepinas/química , Células Cultivadas , Colesterol/farmacologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Dislipidemias/complicações , Feminino , Frutose/farmacologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperinsulinismo/complicações , Hiperinsulinismo/genética , Indóis/química , Rim/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/genética , Receptores para Leptina/genética , Fatores de Transcrição/metabolismo , Triglicerídeos/sangue
3.
J Med Chem ; 50(22): 5245-8, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17902637

RESUMO

Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.


Assuntos
Antirreumáticos/síntese química , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , NF-kappa B/antagonistas & inibidores , Nitrilas/síntese química , Propionatos/síntese química , Administração Oral , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Linhagem Celular , Creatina Quinase/metabolismo , Cristalografia por Raios X , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Luciferases/genética , Camundongos , NF-kappa B/biossíntese , NF-kappa B/genética , Nitrilas/química , Nitrilas/farmacologia , Propionatos/química , Propionatos/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional
4.
Curr Top Med Chem ; 6(2): 103-11, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16454762

RESUMO

The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Pirazóis/uso terapêutico , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/imunologia , Doença Crônica , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
5.
Arthritis Res Ther ; 7(3): R427-38, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15899029

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial proliferation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-kappaB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 transgenic rat and the Lewis rat adjuvant-induced model, after daily oral administration. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, alpha1-acid glycoprotein (alpha1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstrate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-alpha-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-kappaB transcriptional activity.


Assuntos
Artrite Reumatoide/metabolismo , Modelos Animais de Doenças , NF-kappa B/antagonistas & inibidores , Pirazóis/farmacologia , Receptores de Estrogênio/metabolismo , Ativação Transcricional/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Feminino , Humanos , Ligantes , Masculino , NF-kappa B/metabolismo , Pirazóis/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Receptores de Estrogênio/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ativação Transcricional/fisiologia
6.
Am J Physiol Gastrointest Liver Physiol ; 289(2): G267-73, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15817812

RESUMO

Previous studies have demonstrated a dramatic induction of inflammatory gene expression in livers from mice fed a high-fat, high-cholesterol diet containing cholate after 3-5 wk. To determine the contribution of cholate in mediating these inductions, C57BL/6 mice were fed a chow diet supplemented with increasing concentrations of cholic acid (CA) for 5 days. A dose-dependent induction in the hepatic levels of TNF-alpha, VCAM-1, ICAM-1, and SAA-2 mRNA were observed. As positive controls, a dose-dependent repression of cholesterol 7alpha-hydroxylase and a dose-dependent induction of small heterodimer partner (SHP) expression were also observed, suggesting that farnesoid X receptor (FXR) was activated. In addition, ICAM-1 and SHP mRNA levels were also induced in primary human hepatocytes when treated with chenodeoxycholic acid or GW4064, a FXR-selective agonist. The involvement of FXR in CA-induced inflammatory gene expression was further investigated in the human hepatic cell line HepG2. Both ICAM-1 and SHP expression were induced in a dose- and time-dependent manner by treatment with the FXR-selective agonist GW4064. Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA. Finally, the activity of FXR was mapped to a retinoic acid response element (RARE) site containing an imbedded farnesoid X response element (FXRE) on the human ICAM-1 promoter and FXR and retinoid X receptor were demonstrated to bind to this site. Finally, FXR-mediated activation of ICAM-1 could be further enhanced by TNF-alpha cotreatment in hepatocytes, suggesting a potential cooperation between cytokine and bile acid-signaling pathways during hepatic inflammatory events.


Assuntos
Ácidos Cólicos/farmacologia , Proteínas de Ligação a DNA/metabolismo , Hepatócitos/fisiologia , Molécula 1 de Adesão Intercelular/genética , Transdução de Sinais/imunologia , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Hepatócitos/citologia , Humanos , Isoxazóis/farmacologia , Fígado/citologia , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Receptores Citoplasmáticos e Nucleares , Elementos de Resposta/genética , Transdução de Sinais/genética , Fatores de Transcrição/agonistas , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/farmacologia
7.
Proc Natl Acad Sci U S A ; 102(7): 2543-8, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15699342

RESUMO

Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-kappaB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.


Assuntos
NF-kappa B/antagonistas & inibidores , Pirazóis/metabolismo , Pirazóis/farmacologia , Receptores de Estrogênio/metabolismo , Transcrição Gênica/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Linhagem Celular , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Antígeno HLA-B27/genética , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirazóis/química , Ratos , Útero/efeitos dos fármacos , Útero/metabolismo
8.
J Med Chem ; 47(26): 6435-8, 2004 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-15588074

RESUMO

Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.


Assuntos
Anti-Inflamatórios/síntese química , Artrite Reumatoide/tratamento farmacológico , Indazóis/síntese química , Fenóis/síntese química , Receptores de Estrogênio/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Linhagem Celular , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Humanos , Indazóis/química , Indazóis/farmacologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , NF-kappa B/biossíntese , NF-kappa B/genética , Fenóis/química , Fenóis/farmacologia , Ratos , Ratos Endogâmicos Lew , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade
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