Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 30(17): 127387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738984

RESUMO

(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.


Assuntos
Glucosídeos/química , Hipoglicemiantes/química , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 2 de Glucose-Sódio/química , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Glicemia/análise , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Teste de Tolerância a Glucose , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Meia-Vida , Halogenação , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/metabolismo , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 28(21): 3446-3453, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30268701

RESUMO

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 (IC50 = 43 nM for SGLT1 and IC50 = 9 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 10 mg/kg.


Assuntos
Desoxiglucose/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Desoxiglucose/análogos & derivados , Desoxiglucose/síntese química , Desenho de Fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Ratos Zucker , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Inibidores do Transportador 2 de Sódio-Glicose/química , Relação Estrutura-Atividade
3.
J Pharmacol Exp Ther ; 365(3): 676-687, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29674332

RESUMO

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.


Assuntos
Glicemia/metabolismo , Colo/efeitos dos fármacos , Colo/microbiologia , Microbiota/efeitos dos fármacos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Biodiversidade , Colo/metabolismo , Masculino , Camundongos , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo
4.
Bioorg Med Chem Lett ; 28(7): 1182-1187, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29523385

RESUMO

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.


Assuntos
Derivados de Benzeno/farmacologia , Ciclobutanos/farmacologia , Glicosídeos/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Administração Oral , Animais , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/química , Ciclobutanos/administração & dosagem , Ciclobutanos/química , Cães , Relação Dose-Resposta a Droga , Glicosídeos/administração & dosagem , Glicosídeos/química , Haplorrinos , Humanos , Camundongos , Estrutura Molecular , Ratos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-Atividade
5.
SLAS Discov ; 22(4): 433-439, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28328322

RESUMO

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.


Assuntos
Diglicerídeos/análise , Inibidores Enzimáticos/análise , Ensaios de Triagem em Larga Escala , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Acil Coenzima A/metabolismo , Animais , Chlorocebus aethiops , Cromatografia Líquida/métodos , Diglicerídeos/antagonistas & inibidores , Diglicerídeos/biossíntese , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Humanos , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Cinética , Camundongos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , N-Acetilglucosaminiltransferases/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Espectrometria de Massas em Tandem/métodos
6.
Anal Biochem ; 524: 68-75, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27665677

RESUMO

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.


Assuntos
Glicerídeos/metabolismo , Glicerol/metabolismo , Metabolismo dos Lipídeos , N-Acetilglucosaminiltransferases/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Cromatografia Líquida/métodos , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Camundongos
7.
J Org Chem ; 81(8): 3464-9, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27052958

RESUMO

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.

8.
Bioorg Med Chem Lett ; 24(5): 1437-41, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24405703

RESUMO

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.


Assuntos
Compostos Bicíclicos com Pontes/química , Inibidores Enzimáticos/química , Piridazinas/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 21(16): 4762-7, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21767952

RESUMO

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.


Assuntos
Descoberta de Drogas , Frutoquinases/antagonistas & inibidores , Indazóis/farmacologia , Pirazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Indazóis/síntese química , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 20(4): 1432-5, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20089400

RESUMO

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.


Assuntos
Benzoxazinas/síntese química , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenho de Fármacos , Administração Oral , Animais , Benzoxazinas/química , Benzoxazinas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/genética , Cricetinae , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Ratos
12.
J Cardiovasc Pharmacol ; 55(5): 459-68, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20051879

RESUMO

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.


Assuntos
Anticolesterolemiantes/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Endotélio Vascular/efeitos dos fármacos , Quinolinas/efeitos adversos , Vasodilatação/efeitos dos fármacos , Administração Oral , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/farmacocinética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Relação Dose-Resposta a Droga , Injeções Intravenosas , Masculino , Estrutura Molecular , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Coelhos
13.
Org Lett ; 11(13): 2812-5, 2009 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-19507869

RESUMO

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.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Catálise , Proteínas de Transferência de Ésteres de Colesterol/sangue , Cobre/química , Humanos , Indicadores e Reagentes , Cetonas/síntese química , Cetonas/química , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/toxicidade , Oxirredução , Quinolinas/química , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 19(9): 2456-60, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19339179

RESUMO

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.


Assuntos
Química Farmacêutica/métodos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/química , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , Cães , Desenho de Fármacos , Haplorrinos , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Fatores de Risco
15.
J Med Chem ; 52(6): 1768-72, 2009 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-19236017

RESUMO

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.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Administração Oral , Animais , Cricetinae , Gorduras na Dieta/administração & dosagem , Desenho de Fármacos , Humanos , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Camundongos , Quinolinas/síntese química , Espectrometria de Massas por Ionização por Electrospray
17.
Bioorg Med Chem ; 16(6): 3321-41, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18155554

RESUMO

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.


Assuntos
PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazóis/química , Tiadiazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Camundongos , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Ativação Transcricional
18.
J Med Chem ; 50(16): 3954-63, 2007 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-17608467

RESUMO

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.


Assuntos
Hipolipemiantes/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazóis/síntese química , Administração Oral , Animais , Apolipoproteína A-I/genética , Linhagem Celular , Feminino , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia
19.
J Med Chem ; 50(12): 2807-17, 2007 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-17500511

RESUMO

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.


Assuntos
Fenilpropionatos/síntese química , Propionatos/síntese química , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Cálcio/metabolismo , Linhagem Celular , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Propionatos/farmacocinética , Propionatos/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 17(14): 3855-9, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17524639

RESUMO

A novel series of potent and selective PPARdelta agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described.


Assuntos
Glicolatos/farmacologia , PPAR delta/agonistas , Área Sob a Curva , Glicolatos/química , Glicolatos/farmacocinética , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...