RESUMEN
(2S,3R,4R,5S,6R)-2-Aryl-5,5-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols and (2S,3R,4R,5S,6R)-2-aryl-5-fluoro-5-methyl-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols were discovered as dual inhibitors of sodium glucose co-transporter proteins (e.g. SGLT1 and SGLT2) through rational drug design, efficient synthesis, and in vitro and in vivo evaluation. Compound 6g demonstrated potent dual inhibitory activities (IC50 = 96 nM for SGLT1 and IC50 = 1.3 nM for SGLT2). It showed robust inhibition of blood glucose excursion in an oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats when dosed at both 1 mg/kg and 10 mg/kg orally. It also demonstrated postprandial glucose control in db/db mice when dosed orally at 10 mg/kg.
Asunto(s)
Glucósidos/química , Hipoglucemiantes/química , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Transportador 2 de Sodio-Glucosa/química , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Glucemia/análisis , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/patología , Modelos Animales de Enfermedad , Diseño de Fármacos , Prueba de Tolerancia a la Glucosa , Glucósidos/metabolismo , Glucósidos/farmacología , Glucósidos/uso terapéutico , Semivida , Halogenación , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Ratas , Ratas Sprague-Dawley , Transportador 1 de Sodio-Glucosa/metabolismo , Relación Estructura-ActividadRESUMEN
A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50â¯=â¯43â¯nM for SGLT1 and IC50â¯=â¯9â¯nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10â¯mg/kg.
Asunto(s)
Desoxiglucosa/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Administración Oral , Animales , Glucemia/efectos de los fármacos , Desoxiglucosa/administración & dosificación , Desoxiglucosa/análogos & derivados , Desoxiglucosa/síntesis química , Diseño de Fármacos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Macaca fascicularis , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas Sprague-Dawley , Ratas Zucker , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/síntesis química , Inhibidores del Cotransportador de Sodio-Glucosa 2/química , Relación Estructura-ActividadRESUMEN
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/dlâ 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/dlâ 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/metabolismoRESUMEN
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 (IC50â¯=â¯45â¯nM), and excellent potency at SGLT2 (IC50â¯=â¯1â¯nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (Fâ¯=â¯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 24â¯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-ActividadRESUMEN
Monoacylglycerol acyltransferase enzymes (MGAT1, MGAT2, and MGAT3) convert monoacylglycerol to diacylglycerol (DAG). MGAT1 and MGAT2 are both implicated in obesity-related metabolic diseases. Conventional MGAT enzyme assays use radioactive substrates, wherein the product of the MGAT-catalyzed reaction is usually resolved by time-consuming thin layer chromatography (TLC) analysis. Furthermore, microsomal membrane preparations typically contain endogenous diacylglycerol acyltransferase (DGAT) from the host cells, and these DGAT activities can further acylate DAG to form triglyceride (TG). Our mass spectrometry (liquid chromatography-tandem mass spectrometry, or LC/MS/MS) MGAT2 assay measures human recombinant MGAT2-catalyzed formation of didecanoyl-glycerol from 1-decanoyl-rac-glycerol and decanoyl-CoA, to produce predominantly 1,3-didecanoyl-glycerol. Unlike 1,2-DAG, 1,3-didecanoyl-glycerol is proved to be not susceptible to further acylation to TG. 1,3-Didecanoyl-glycerol product can be readily solubilized and directly subjected to high-throughput mass spectrometry (HTMS) without further extraction in a 384-well format. We also have established the LC/MS/MS MGAT activity assay in the intestinal microsomes from various species. Our assay is proved to be highly sensitive, and thus it allows measurement of endogenous MGAT activity in cell lysates and tissue preparations. The implementation of the HTMS MGAT activity assay has facilitated the robust screening and evaluation of MGAT inhibitors for the treatment of metabolic diseases.
Asunto(s)
Diglicéridos/análisis , Inhibidores Enzimáticos/análisis , Ensayos Analíticos de Alto Rendimiento , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Acilcoenzima A/metabolismo , Animales , Chlorocebus aethiops , Cromatografía Liquida/métodos , Diglicéridos/antagonistas & inhibidores , Diglicéridos/biosíntesis , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Intestinos/efectos de los fármacos , Intestinos/enzimología , Cinética , Ratones , Microsomas/efectos de los fármacos , Microsomas/enzimología , N-Acetilglucosaminiltransferasas/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Espectrometría de Masas en Tándem/métodosRESUMEN
Monoacylglycerol acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DAG) from free fatty acids (FFA) and sn-monoacylglycerol (MG), the two major hydrolysis products of dietary fat. To demonstrate MGAT2-mediated cellular activity of triglyceride (TG) synthesis, we utilized 1-oleoyl-glycerol-d5 as a substrate to trace MGAT2-driven 1-oleoyl-glycerol-d5 incorporation into TG in HEK293 cells stably expressing human MGAT2. The oleoyl-glycerol-d5 incorporated major TG species were then quantified by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) in a 96-well format. Conventional MGAT2 target-engagement in vivo assays measure the elevation of total plasma TG by orally dosing a bolus of TG oil. We developed a novel LC/ESI/MS/MS-based fat absorption assay to assess the ability of MGAT2 inhibitors to inhibit fat absorption in CD1 mice by a meal tolerance test consisting of a mixture of liquid Boost plus® and 0.59 g/kg U13C-TG oil. The newly resynthesized plasma heavy TGs containing three 13C in the glycerol backbone and two U13C-acyl-chains, which represented the digested, absorbed and resynthesized TGs, were then quantitated by LC/ESI/MS/MS. With this assay, we identified a potent MGAT2 inhibitor that blocked MGAT2-mediated activity in vitro and in vivo. The use of 1-oleoyl-glycerol-d5 and U13C-TG oil followed by LC/ESI/MS/MS detection of stable-isotopic labeled DAG, TG, or glycerol provides a wide range of applications to study pathophysiological regulation of the monoacylglycerol pathway and MGAT2 activity.
Asunto(s)
Glicéridos/metabolismo , Glicerol/metabolismo , Metabolismo de los Lípidos , N-Acetilglucosaminiltransferasas/metabolismo , Espectrometría de Masas en Tándem/métodos , Animales , Cromatografía Liquida/métodos , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , RatonesRESUMEN
Phosphonium salt-activated, Pd-catalyzed Suzuki-Miyaura and Sonogashira cross-coupling reactions of cyclic 1,3-diones in the synthesis of ß-substituted cyclic enones are described. These transformations exhibit good isolated yield and high generality with respect to both substrates and coupling partners. Extension of the substrate scope to cyclic 1,3-dione equivalents, such as 2-cyanocyclohexanone (4), is also briefly examined.
RESUMEN
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Inhibidores Enzimáticos/química , Piridazinas/química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Obesidad/tratamiento farmacológico , Piridazinas/farmacocinética , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-ActividadRESUMEN
A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Piperidinas/química , Piperidinas/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Urea/análogos & derivados , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Dieta , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Piperidinas/metabolismo , Unión Proteica , Ratas , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-Actividad , Urea/metabolismo , Urea/farmacologíaRESUMEN
A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.
Asunto(s)
Descubrimiento de Drogas , Fructoquinasas/antagonistas & inhibidores , Indazoles/farmacología , Pirazoles/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Indazoles/síntesis química , Indazoles/química , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Torcetrapib, a prototype cholesteryl ester transfer protein (CETP) inhibitor with potential for decreasing atherosclerotic disease, increased cardiovascular events in clinical trials. The identified hypertensive and aldosterone-elevating actions of torcetrapib may not fully account for this elevated cardiovascular risk. Therefore, we evaluated the effects of torcetrapib on endothelial mediated vasodilation in vivo. METHODS AND RESULTS: In vivo endothelial mediated vasodilation was assessed using ultrasound imaging of acetylcholine-induced changes in rabbit central ear artery diameter. Torcetrapib, in addition to producing hypertension and baseline vasoconstriction, markedly inhibited acetylcholine-induced vasodilation. A structurally distinct CETP inhibitor, JNJ-28545595, did not affect endothelial function despite producing similar degrees of CETP inhibition and high-density lipoprotein elevation. Nitroprusside normalized torcetrapib's basal vasoconstriction and elicited dose-dependent vasodilation of norepinephrine preconstricted arteries in torcetrapib-treated animals, indicating torcetrapib did not impair smooth muscle function. CONCLUSIONS: Torcetrapib significantly impairs endothelial function in vivo, independent of CETP inhibition and high-density lipoprotein elevation. Given the well-documented association of endothelial dysfunction with cardiovascular disease and risk, this activity of torcetrapib may have contributed to increased cardiovascular risk in clinical trials.
Asunto(s)
Anticolesterolemiantes/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Endotelio Vascular/efectos de los fármacos , Quinolinas/efectos adversos , Vasodilatación/efectos de los fármacos , Administración Oral , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacocinética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Relación Dosis-Respuesta a Droga , Inyecciones Intravenosas , Masculino , Estructura Molecular , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , ConejosRESUMEN
2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC50=26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F=53%) and long human liver microsome stability (t(1/2)=62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.
Asunto(s)
Benzoxazinas/síntesis química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Diseño de Fármacos , Administración Oral , Animales , Benzoxazinas/química , Benzoxazinas/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/genética , Cricetinae , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Transgénicos , Estructura Molecular , RatasRESUMEN
The asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol (compound 11), a cholesteryl ester transfer protein inhibitor, is accomplished. The asymmetric center is established via the chiral reduction of ketone 4 employing Corey's (R)-Me CBS oxazaborolidine reagent. The tetrahydroquinoline core of the molecule is established via a Cu-mediated intramolecular amination reaction. The preparation of the prochiral ketone 4 has also been improved by eliminating the use of a hazardous aryltin reagent.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Catálisis , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Cobre/química , Humanos , Indicadores y Reactivos , Cetonas/síntesis química , Cetonas/química , Ratones , Ratones Transgénicos , Estructura Molecular , Compuestos Orgánicos de Estaño/química , Compuestos Orgánicos de Estaño/toxicidad , Oxidación-Reducción , Quinolinas/química , EstereoisomerismoRESUMEN
Tetrahydroquinoline A is a potent inhibitor of the cholesterol ester transfer protein (CETP), a target for the treatment of low HDL-C and atherosclerosis. Low HDL-C has been identified as a key risk factor for cardiovascular disease in addition to high LDL-C, the target of the statin drugs. Tetrahydroquinoline A inhibits partially purified CETP with an IC(50) of 39nM. The preparation of a series of potent inhibitors of CETP designed around a 1,2,3,4-tetrahydroquinoline platform will be discussed.
Asunto(s)
Química Farmacéutica/métodos , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/química , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/prevención & control , HDL-Colesterol/metabolismo , Perros , Diseño de Fármacos , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Factores de RiesgoRESUMEN
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Administración Oral , Animales , Cricetinae , Grasas de la Dieta/administración & dosificación , Diseño de Fármacos , Humanos , Macaca fascicularis , Espectroscopía de Resonancia Magnética , Ratones , Quinolinas/síntesis química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.
Asunto(s)
Glicolatos/síntesis química , Glicolatos/farmacología , PPAR delta/agonistas , Técnicas Químicas Combinatorias , Diseño de Fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Glicolatos/química , Humanos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.
Asunto(s)
PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazoles/química , Tiadiazoles/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Regulación de la Expresión Génica/efectos de los fármacos , Síndrome Metabólico/tratamiento farmacológico , Ratones , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinética , Activación TranscripcionalRESUMEN
Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.
Asunto(s)
Hipolipemiantes/síntesis química , PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazoles/síntesis química , Administración Oral , Animales , Apolipoproteína A-I/genética , Línea Celular , Femenino , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Resistencia a la Insulina , Masculino , Ratones , Ratones Obesos , Ratones Transgénicos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiadiazoles/farmacocinética , Tiadiazoles/farmacologíaRESUMEN
High-throughput screening of a subset of the J&J compound library containing the carboxylic acid functional group uncovered a bromophenyl derivative as a moderate potent GPR40 agonist. Chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Among them, 22 and 24 behaved as full agonists when compared to the endogenous GPR40 ligand linolenic acid in a functional Ca+2 flux assay in HEK cells expressing GPR40 receptor. Several GPR40 agonists have also demonstrated the ability to induce glucose-mediated insulin secretion in the mouse MIN6 pancreatic beta-cell line. Our data supports the hypothesis that GPR40 may play an important role in fatty acid-mediated glucose-dependent insulin secretion. Compound 22 exhibited good pharmacokinetic profile in rat and may serve as a good candidate for in vivo study and may help to determine if GPR40 agonists would be beneficial in the treatment of type II diabetes.
Asunto(s)
Fenilpropionatos/síntesis química , Propionatos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Disponibilidad Biológica , Calcio/metabolismo , Línea Celular , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Ratones , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacología , Propionatos/farmacocinética , Propionatos/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of potent and selective PPARdelta agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described.