RESUMEN
FXR is a member of the nuclear receptor superfamily, which regulates the expression of various genes involved in bile acid, lipid and glucose metabolism. Targeting FXR with small molecules has been exploited to treat lipid-related disorders and diseases such as cholestasis, gallstones and hepatic disorders. In this work, we expand the existing pool of known FXR agonists using a fast hit-to-lead structure-based pharmacophore and docking screening protocol. A set of 25 molecules was selected after screening a large database of commercial chemicals, and experimental tests were carried out to demonstrate their ability to activate FXR. Three novel FXR agonists are reported, namely, one full agonist, more efficient than the endogenous ligand chenodeoxycholic acid, and two partial agonists.
RESUMEN
Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism.
Asunto(s)
Modelos Moleculares , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Relación Dosis-Respuesta a Droga , Células HEK293 , Células Hep G2 , Humanos , Estructura Molecular , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , ARN Neoplásico/efectos de los fármacos , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Células Tumorales CultivadasRESUMEN
PPARα is a ligand activated transcription factor belonging to the nuclear receptor subfamily, involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation is important in steatosis, inflammation and fibrosis in preclinical models of non-alcoholic fatty liver disease identifying a new potential therapeutic area. In this work, three series of clofibric acid analogues conjugated with naphthyl, quinolin, chloroquinolin and anthracenyl scaffolds were synthesized. In an effort to obtain new compounds active as PPARα agonists, these molecules were evaluated for PPARα transactivation activity. Naphthyl and quinolin derivatives showed a good activation of PPARα; noteworthy, optically active naphthyl derivatives activated PPARα better than corresponding parent compound.
Asunto(s)
Ácido Clofíbrico/análogos & derivados , PPAR alfa/agonistas , Ácido Clofíbrico/farmacología , HumanosRESUMEN
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and trans-stilbene, chalcone, and other lipophilic groups were synthesized. They were evaluated for PPARα transactivation activity; all branched derivatives showed an increase of the transcriptional activity of receptor compared to the linear ones. Noteworthy, stilbene and benzophenone branched derivatives activated the PPARα better than clofibric acid.
Asunto(s)
Chalcona/química , Ácido Clofíbrico/farmacología , PPAR alfa/agonistas , Estilbenos/química , Línea Celular , Chalcona/farmacología , Ácido Clofíbrico/química , Humanos , Estructura Molecular , Estilbenos/farmacología , Relación Estructura-Actividad , Activación Transcripcional/efectos de los fármacosRESUMEN
The identification of novel PPAR ligands represents an attractive research to fully understand the complex biological pathways regulated by these receptors. Selective PPAR modulators, inverse agonists and antagonists of three PPAR isoforms could help to clarify biological effects on lipid and glucose homeostasis. Here we describe the identification of a group of N-(methylsulfonyl)amides, derived from PPARα agonist carboxylic acids. Transactivation and FRET assay confirmed an antagonist behaviour on PPARα for some of these compounds, with submicromolar IC(50). A preliminary analysis on selectivity α/γ revealed different profiles of inhibition or activation.
Asunto(s)
PPAR alfa/antagonistas & inhibidores , Sulfonamidas/farmacología , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ.
Asunto(s)
Clofibrato/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Clofibrato/síntesis química , Clofibrato/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A new series of gemfibrozil analogues conjugated with α-asarone, trans-stilbene, chalcone, and their bioisosteric modifications were synthesized and evaluated to develop PPARα agonists. In this attempt, we have removed the methyls on the phenyl ring of gemfibrozil and introduced the above scaffolds in para position synthesizing two series of derivatives, keeping the dimethylpentanoic skeleton of gemfibrozil unaltered or demethylated. Four compounds exhibited good activation of the PPARα receptor and were also screened for their activity on PPARα-regulated gene CPT1A.
Asunto(s)
Carnitina O-Palmitoiltransferasa/genética , Ácidos Grasos/metabolismo , Gemfibrozilo/análogos & derivados , Gemfibrozilo/farmacología , PPAR alfa/agonistas , PPAR alfa/metabolismo , Células Hep G2 , Humanos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The discovery of PPAR antagonists is emerging as an useful tool for elucidating the biological role of the receptor. Here we report the identification of N-(phenylsulfonyl)amides containing the benzothiazole scaffold, a novel class of potent PPARα antagonists obtained from chemical modification of carboxylic acid agonists. In this work, a group of phenylsulfonamides were synthesized and in vitro evaluated against the agonistic effect of GW7647; they showed an inhibitory effect on PPARα activation, with best compounds revealing a dose-dependent antagonistic profile. Some of these antagonists showed also an inhibitory effect on CPT1A pattern expression.
Asunto(s)
Benzotiazoles/farmacología , PPAR alfa/antagonistas & inhibidores , Sulfonamidas/farmacología , Benzotiazoles/síntesis química , Benzotiazoles/química , Butiratos/farmacología , Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Carnitina O-Palmitoiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Compuestos de Fenilurea/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.