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1.
J Med Chem ; 63(8): 3868-3880, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31940200

RESUMO

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.


Assuntos
Benzotiazóis/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Dieta Hiperlipídica/efeitos adversos , Isoxazóis/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Benzotiazóis/química , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/uso terapêutico , Cães , Humanos , Isoxazóis/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Estrutura Terciária de Proteína , Ratos , Resultado do Tratamento
2.
Hepatol Commun ; 3(8): 1085-1097, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31388629

RESUMO

Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid-derived FXR agonist obeticholic acid (OCA) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of the novel nonbile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (Stelic animal model [STAM]), tropifexor reversed established fibrosis and reduced the nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant obese NASH model (amylin liver NASH model [AMLN]), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment that included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.

3.
J Med Chem ; 60(24): 9960-9973, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29148806

RESUMO

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.


Assuntos
Benzotiazóis/farmacologia , Colestase/tratamento farmacológico , Isoxazóis/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Administração Oral , Animais , Benzotiazóis/uso terapêutico , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoxazóis/uso terapêutico , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Piperidinas/química , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
4.
Bioorg Med Chem Lett ; 19(15): 4437-40, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19482472

RESUMO

The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.


Assuntos
Compostos Azabicíclicos/síntese química , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Tiazolidinas/síntese química , Compostos Azabicíclicos/farmacologia , Catálise , Diabetes Mellitus/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Nitrilas/farmacologia , Estrutura Terciária de Proteína , Pirrolidinas/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazolidinas/farmacologia , Fatores de Tempo
5.
Cancer Res ; 62(12): 3485-92, 2002 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12067992

RESUMO

Forty-eight hereditary nonpolyposis colorectal carcinoma (HNPCC) families for which a tumor sample was available were evaluated for the presence of germ-line mutations in MSH2 and MLH1, tumor microsatellite instability (MSI), and where possible, expression of MSH2 and MLH1 in tumors by immunohistochemistry. Fourteen of 48 of the families had a germ-line mutation in either MSH2 or MLH1 that could be detected by genomic DNA sequencing, and 28 of 48 of the families had MSI-H tumors. Four additional families showed loss of expression of MSH2, and one additional family showed loss of expression of MLH1 but did not have germ-line mutations in MSH2 or MLH1 that could be detected by DNA sequencing. MSI-H, as defined using the National Cancer Institute recommended five-microsatellite panel, had a 100% sensitivity for identifying samples having MSH2 or MLH1 mutations or loss of expression. In contrast, loss of MSH2 and MLH1 expression did not identify all samples having germ-line mutations in MSH2 or MLH1, because in five cases, a mutant protein product was expressed that could be detected by IHC. A combination of the Bethesda criteria for HNPCC and an MSI-H phenotype defined the smallest number of cases having all of the germ-line MSH2 and MLH1 mutations that could be detected by DNA sequencing.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Humanos , Imuno-Histoquímica , Repetições de Microssatélites/genética , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/biossíntese , Proteínas Nucleares , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/biossíntese
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