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1.
J Pharmacol Exp Ther ; 365(3): 676-687, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29674332

RESUMEN

The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (GI) luminal glucose and tolerability, and this was evaluated in slc5a1-/- mice or with a potent dual inhibitor (compound 8; SGLT1 Ki = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 Ki = 0.4 ± 0.2 nM). 13C6-glucose uptake was quantified in slc5a1-/- mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57Bl/6 mice. The blood 13C6-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 ± 6 vs. 64 ± 6 mg/dl⋅h in wild-type vs. slc5a1-/- mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 ± 3 vs. 249 ± 5 mg/dl⋅h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL/6 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.


Asunto(s)
Glucemia/metabolismo , Colon/efectos de los fármacos , Colon/microbiología , Microbiota/efectos de los fármacos , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Biodiversidad , Colon/metabolismo , Masculino , Ratones , Ratas , Inhibidores del Cotransportador de Sodio-Glucosa 2/metabolismo
2.
Bioorg Med Chem Lett ; 28(7): 1182-1187, 2018 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-29523385

RESUMEN

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.


Asunto(s)
Derivados del Benceno/farmacología , Ciclobutanos/farmacología , Glicósidos/farmacología , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Administración Oral , Animales , Derivados del Benceno/administración & dosificación , Derivados del Benceno/química , Ciclobutanos/administración & dosificación , Ciclobutanos/química , Perros , Relación Dosis-Respuesta a Droga , Glicósidos/administración & dosificación , Glicósidos/química , Haplorrinos , Humanos , Ratones , Estructura Molecular , Ratas , Transportador 1 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Relación Estructura-Actividad
3.
J Lipid Res ; 53(6): 1106-16, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22493088

RESUMEN

Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with (13)C(3)-D(5)-glycerol or (13)C(18)-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that (13)C(3)-D(5)-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, (13)C(18)-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D(5)-glycerol to mice and measured plasma levels of D(5)-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D(5)-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered (13)C(18)-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/metabolismo , Pruebas de Enzimas/métodos , Glicerol/metabolismo , Hígado/enzimología , Ácido Oléico/metabolismo , Animales , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diacilglicerol O-Acetiltransferasa/genética , Inhibidores Enzimáticos/farmacología , Esterificación/efectos de los fármacos , Ácidos Grasos/biosíntesis , Ácidos Grasos/metabolismo , Células Hep G2 , Humanos , Marcaje Isotópico , Lipoproteínas VLDL/metabolismo , Masculino , Ratones , Oligonucleótidos Antisentido/genética , Triglicéridos/biosíntesis
4.
Eur J Med Chem ; 138: 830-853, 2017 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-28735214

RESUMEN

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Indazoles/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Indazoles/administración & dosificación , Indazoles/química , Ligandos , Masculino , Ratones , Ratones Obesos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Relación Estructura-Actividad , Receptor Relacionado con Estrógeno ERRalfa
5.
J Med Chem ; 54(3): 788-808, 2011 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-21218783

RESUMEN

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 µM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.


Asunto(s)
Éteres/síntesis química , Hipoglucemiantes/síntesis química , Receptores de Estrógenos/metabolismo , Tiazolidinedionas/síntesis química , Administración Oral , Animales , Unión Competitiva , Disponibilidad Biológica , Cristalografía por Rayos X , Diabetes Mellitus/tratamiento farmacológico , Perros , Éteres/farmacocinética , Éteres/farmacología , Femenino , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina , Ligandos , Macaca fascicularis , Masculino , Ratones , Ratones Noqueados , Modelos Moleculares , Estructura Molecular , Obesidad/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/genética , Relación Estructura-Actividad , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/farmacología , Triglicéridos/sangre , Receptor Relacionado con Estrógeno ERRalfa
6.
Bioorg Med Chem Lett ; 17(17): 4861-5, 2007 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-17611106

RESUMEN

A series of 4-amino-6-piperazin-1-yl-pyrimidine-5-carbaldehyde oximes has been discovered and developed as potent FLT3 tyrosine kinase inhibitors. The series exhibited potent antiproliferative activity against both an FLT3 ITD-mutated human leukemic cell line as well as a wild-type FLT3 BaF(3) expressed cell line. The structure-activity relationship of this class of compounds is described.


Asunto(s)
Aldehídos/química , Química Farmacéutica/métodos , Oximas/síntesis química , Oximas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Mutación , Oximas/química , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 13(4): 637-40, 2003 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-12639547

RESUMEN

We have identified a novel class of 6-thiazolylquinazolines as potent and selective inhibitors of both ErbB-2 and EGFR tyrosine kinase activity, with IC(50) values in the nanomolar range. These compounds inhibited the growth of both EGFR (HN5) and ErbB-2 (BT474) over-expressing human tumor cell lines in vitro. Using xenograft models of the same cell lines, we found that the compounds given orally inhibited in vivo tumor growth significantly compared with control animals.


Asunto(s)
Antineoplásicos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Receptor ErbB-2/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos , Neoplasias Experimentales/tratamiento farmacológico , Quinazolinas/farmacología , Relación Estructura-Actividad , Trasplante Heterólogo
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