RESUMEN
In order to investigate SAR regarding proximal phenyl ring in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on proximal phenyl ring was conducted. During a series of lead optimization efforts, ortho-allyloxyphenyl 10p or ortho-hydroxyphenyl 11a showed subnanomolar inhibitory activity against hSGLT2.
Asunto(s)
Glucósidos/síntesis química , Hipoglucemiantes/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiazoles/síntesis química , Animales , Transporte Biológico/efectos de los fármacos , Células CHO , Radioisótopos de Carbono , Cricetulus , Expresión Génica , Glucósidos/farmacología , Humanos , Hipoglucemiantes/farmacología , Metilglucósidos/metabolismo , Proteínas Recombinantes/química , Bibliotecas de Moléculas Pequeñas/farmacología , Transportador 2 de Sodio-Glucosa/química , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
In order to investigate SAR regarding glucose moiety in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on glucose was conducted to explore potential utility as a suitable replacement of glucose per se. Among the compounds prepared, deshydroxy 29 (IC(50)=7.01nM) demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date. But, none of the compounds were better than the parent molecule 5 (IC(50)=1.75nM).
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Glicósidos/química , Glicósidos/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa/metabolismo , Diabetes Mellitus/enzimología , Humanos , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted.
RESUMEN
Novel C-aryl glucoside SGLT2 inhibitors containing pyrimidine motif were designed and synthesized for biological evaluation. Among the compounds assayed, pyrimidine containing methylthio moiety 11 g demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=10.7 nM).
Asunto(s)
Glucósidos/química , Glucósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Humanos , Hipoglucemiantes/farmacología , Concentración 50 Inhibidora , Ratones , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Structure-activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity.
Asunto(s)
Receptor Cannabinoide CB1/antagonistas & inhibidores , Tiadiazoles/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/química , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacocinéticaRESUMEN
With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion. On the other hand, a series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl gluconolactone 9 and 2-lithiothiazole. Biological activities of the compounds thus prepared were evaluated by the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzylthiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors useful for pharmacotherapy.
Asunto(s)
Piridazinas/química , Piridazinas/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa/metabolismo , Tiazoles/química , Tiazoles/farmacología , Humanos , Piridazinas/síntesis química , Relación Estructura-Actividad , Tiazoles/síntesis químicaRESUMEN
Novel C-aryl glucoside SGLT2 inhibitors containing pyridazine motif were designed and synthesized for biological evaluation. Among the compounds tested, pyridazine containing methylthio moiety 22l or thiadiazole ring 22ah showed the best in vitro inhibitory activities in this series (IC(50)=13.4, 11.4nM, respectively) against SGLT2 to date. Subsequently, compound 22l exhibited reasonable urinary glucose excretion and glucosuria in normal SD rats, thereby demonstrating that this pyridazine series possesses both in vitro SGLT2 inhibition and in vivo efficacy, albeit to a lower degree.
Asunto(s)
Glucósidos/farmacología , Hipoglucemiantes/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Ratas , Ratas Sprague-Dawley , Transportador 2 de Sodio-GlucosaRESUMEN
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC(50) = 3.51-7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.
Asunto(s)
Glucósidos/farmacología , Hipoglucemiantes/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiadiazoles/farmacología , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Diseño de Fármacos , Glucósidos/síntesis química , Glucósidos/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Ratones Endogámicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Transportador 2 de Sodio-Glucosa/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/químicaRESUMEN
Numerous research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, proved to be efficacious in human for the treatment of obesity. In the present study, a series of 1,2,4-triazole-containing diarylpyrazolyl carboxamides based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. The structure-activity relationship studies demonstrated that incorporation of 1,2,4-triazole ring onto the pyrazole scaffold via a methylene linker led to a significant improvement for CB1 receptor binding affinity. Importantly, these analogues also exhibited excellent selectivity for CB1 receptor over CB2 receptor.
Asunto(s)
Pirazoles/química , Pirazoles/farmacología , Receptor Cannabinoide CB1/metabolismo , Triazoles/química , Triazoles/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Pirazoles/síntesis química , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Triazoles/síntesis químicaRESUMEN
Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of pentacycle derivatives. Five of the new compounds which displayed high in vitro rCB1 binding affinities were assayed for binding to hCB2 receptor. Noticeably, 2-(5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole (16l) demonstrated good binding affinity and decent selectivity for rCB1 receptor (IC(50)=1.72 nM, hCB2/rCB1=142).
Asunto(s)
Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Diseño de Fármacos , Humanos , Ligandos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Cannabinoid CB1 receptors have been the avenue of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of substituted pyrimidines based on chemical structure of Merck's taranabant, a cannabinoid CB1 receptor inverse agonist. Noticeably, N4-((2S,3S)-3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-yl)-N6-butylpyrimidine-4,6-diamine (13b) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50)=16.3nM, CB2/CB1=181.6).
Asunto(s)
Fármacos Antiobesidad/química , Pirimidinas/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Ligandos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismoRESUMEN
Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of oxadiazole-diarylpyrazole 4-carboxamides. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-phenyl-1H-pyrazole-4-carboxamide (12q) and 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-1H-pyrazole-4-carboxamide (12r) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50) = 1.35 nM, CB2/CB1 = 286 for 12q; IC(50) = 1.46 nM, CB2/CB1 = 256 for 12r).
Asunto(s)
Fármacos Antiobesidad/síntesis química , Oxadiazoles/síntesis química , Pirazoles/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Células CHO , Cricetinae , Cricetulus , Concentración 50 Inhibidora , Ligandos , Obesidad/tratamiento farmacológico , Oxadiazoles/química , Oxadiazoles/farmacología , Pirazoles/química , Pirazoles/farmacología , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , TransfecciónRESUMEN
A myriad of research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, was discovered for an obesity treatment. In this research, extended series, based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. In the present study, N-piperidinylcarboxamide group of rimonabant was replaced with the corresponding sulfonamide, imide, N-methyl imide and methylenediamide, respectively. The SAR studies to optimize the CB1 binding affinity led to the potent imide derivatives. The in vivo efficacy test of a derivative (16f) gave a promising result for this novel scaffold. In order to explore physicochemical properties (hydrophobic, steric and electronic) of the representative imide derivatives responsible for their CB1 receptor binding affinity, quantitative structure activity relationship (QSAR) studies were performed. Hansch QSAR models, which were moderate in the explanation for SAR, were generated with hydrophobic, steric and electronic properties of substituents. Especially, the Taft Es-based parabolic model was obtained with the best correlation result (r(2)=0.846).
Asunto(s)
Piperidinas/química , Piperidinas/farmacología , Pirazoles/química , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Diseño de Fármacos , Imidas/síntesis química , Imidas/química , Imidas/farmacología , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Piperidinas/síntesis química , Unión Proteica , Pirazoles/síntesis química , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/química , RimonabantRESUMEN
Since the CB1 receptor antagonist SR141716 (rimonabant) was reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target in the treatment of obesity. Several series of derivatives based on diarylimidazolyl oxadiazole and thiadiazole scaffolds were synthesized and tested for CB1 receptor binding affinity. SAR studies directed toward the optimization of imidazole scaffolds resulted in the discovery of 10s which showed highest potency for CB1 receptor binding affinity (IC(50)=1.91nM) prepared to date.
Asunto(s)
Oxadiazoles/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tiadiazoles/síntesis química , Animales , Imidazoles , Concentración 50 Inhibidora , Obesidad/tratamiento farmacológico , Oxadiazoles/farmacología , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacologíaRESUMEN
BACKGROUND: Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. DISCUSSION: In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity. RESULTS: The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.
Asunto(s)
Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Oxadiazoles/química , Pirazoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tiadiazoles/química , Administración Oral , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Sitios de Unión , Disponibilidad Biológica , Simulación por Computador , Humanos , Ratones , Oxadiazoles/farmacocinética , Oxadiazoles/uso terapéutico , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tiadiazoles/farmacocinética , Tiadiazoles/uso terapéuticoRESUMEN
Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.
Asunto(s)
Obesidad/tratamiento farmacológico , Oxadiazoles/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Simulación por Computador , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Cannabinoid CB1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed a new series of tetrazole-biarylpyrazoles. The various analogues were efficiently prepared and bio-assayed for binding to cannabinoid CB1 receptor. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, cyclopentyl-tetrazole (9a) demonstrated good binding affinity and selectivity for CB1 receptor (IC(50)=11.6nM and CB2/CB1=366).
Asunto(s)
Fármacos Antiobesidad/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tetrazoles/farmacología , Fármacos Antiobesidad/síntesis química , Unión Competitiva , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ligandos , Modelos Químicos , Pirazoles/síntesis química , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tetrazoles/síntesis químicaRESUMEN
After the CB1 receptor antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Several series of urea, carbamate, amide, sulfonamide and oxalamide derivatives based on 1-benzhydrylpiperazine scaffold were synthesized and tested for CB1 receptor binding affinity. The SAR studies to optimize the CB1 binding affinity led to the potent urea derivatives. After the additional SAR studies to optimize the substituents of diphenyl rings, the combination of 2-chlorophenyl and 4-chlorophenyl turned out to be the most potent scaffold. The CB2 binding affinity assay as well as functional assay was also conducted on these compounds. Herein we wish to introduce several novel CB1 antagonists with IC(50) values less than 100 nM for the CB1 receptor binding.
Asunto(s)
Diseño de Fármacos , Piperazinas/síntesis química , Piperazinas/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Animales , Humanos , Ligandos , Masculino , Estructura Molecular , Piperazina , Piperazinas/química , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
CO2 photoacoustic spectroscopy was employed to analyze kinetically the CO2/CH4 reaction catalyzed by 14 wt% Ni/Al2O3 and 14 wt% Ni/TiO2. The catalytic reaction was carried out in the temperature range of 673-923 K at various partial pressures of CO2 and CH4 (40 Torr total pressure) in a closed-circulating reactor system. The CO2 photoacoustic signal, measured by using a differential photoacoustic cell, was recorded as a function of reaction time. Under these conditions, Al203 and TiO2 used as supports do not promote the reaction as noted by the lack of changes in the CO2 photoacoustic signal. Reactions run in the presence of H2-reduced supported Ni catalysts are associated with significant time dependent changes in the CO2 photoacoustic signal, while processes carried out in the presence of unreduced catalysts do not. Changes in the CO2 photoacoustic signal at early reaction times provide precise data for the rate of CO2 disappearance. The rate of CO2 disappearance is observed to increase with increasing temperature in the range of 673-923 K. Apparent activation energies for CO2 consumption were calculated to be 15.4 kcal mol(-1) for the Ni/Al2O3- and 14.3 kcal mol(-1) for the Ni/TiO2-catalyzed reactions. Reaction orders, determined from initial rates of CO2 disappearance at 873 K, were found to be 0.48 in CH4 and 0.45 in CO2 for the Ni/Al2O3-promoted process, and 0.38 in CH4 and 0.32 in CO2 for the Ni/TiO2-catalyzed reaction. The results of this effort were compared with those reported previously and were used to construct a mechanism for the low pressure CO2/CH4 reaction.
RESUMEN
Dioxins are a class of polyhalogenated aromatic hydrocarbons that induce a wide spectrum of toxic responses in experimental animals. In this study, 2,3,7,8-tetrachlorobenzo-p-dioxin (TCDD) was exposed to two SD rat groups; one group for short-term exposure at a single dose of 1, 10, 20 and 50 mug/kg body weight (group 1) and the other for long-term exposure at daily and-low dose of 0.01, 0.1, 1 and 2.5 microg/kg body weight (group 2) for a month. Two-dimensional electrophoresis (2-DE) was utilized to resolve the protein profile of rat liver exposed to TCDD at different doses. In the analysis of 2-DE of the group 1, two new-expressed spots and seven volume-increased spots were detected and identified by ESI-Q-TOF MS/MS; especially, proteasome subunit beta type 3 was increased in all doses. In addition, in the group 2, six volume-increased spots were screened; particularly, histidine triad nucleotide binding protein was increased in both 0.1 microg/kg dose and 1 microg/kg dose. The identified proteins were confirmed using Western blot. Among the identified proteins, apolipoprotein A-IV may protect lipid peroxidation and atherosclerosis induced by TCDD exposure and the expression level of phosphoglycerate mutase increases due to hyperthyroidism induced by TCDD exposure.