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1.
PLoS One ; 15(12): e0240338, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33306682

RESUMEN

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRß agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRß-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRß and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRß agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores beta de Hormona Tiroidea/agonistas , Transcripción Genética/efectos de los fármacos , Acetatos/farmacología , Acetatos/uso terapéutico , Proteína 4 Similar a la Angiopoyetina/metabolismo , Animales , Línea Celular Tumoral , LDL-Colesterol/sangre , LDL-Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hepatocitos , Humanos , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Malato Deshidrogenasa/genética , Malato Deshidrogenasa/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Fenoles/farmacología , Fenoles/uso terapéutico , Cultivo Primario de Células , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Uracilo/análogos & derivados , Uracilo/farmacología , Uracilo/uso terapéutico
2.
J Med Chem ; 57(5): 1880-92, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24144360

RESUMEN

Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Cristalografía por Rayos X , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética
3.
Bioorg Med Chem Lett ; 22(13): 4431-6, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22542193

RESUMEN

Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.


Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
4.
Bioorg Med Chem Lett ; 22(13): 4437-43, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22633687

RESUMEN

Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(50)>20 µM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.


Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Indoles/química , Sulfonamidas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Hígado/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
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