RESUMEN
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
Asunto(s)
Isoquinolinas/farmacología , Pirazinas/farmacología , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Isoquinolinas/química , Pirroles/química , Pirroles/síntesis química , Receptor de Serotonina 5-HT2C/química , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Animales , Semivida , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Masculino , Pirroles/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/química , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/farmacocinética , Relación Estructura-ActividadRESUMEN
Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
Asunto(s)
Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Quinazolinonas/química , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/química , Administración Oral , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Humanos , Masculino , Obesidad/metabolismo , Unión Proteica/fisiología , Quinazolinonas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/metabolismoRESUMEN
Troglitazone (TGZ) induced hepatotoxicity has been linked to cytochrome P450 (CYP)-catalyzed reactive metabolite formation. Therefore, the kinetics and CYP specificity of reactive metabolite formation were studied using dansyl glutathione (dGSH) as a trapping agent after incubation of TGZ with human liver microsomes (HLM) and recombinant human CYP proteins. CYP2C8 exhibited the highest rate of TGZ adduct (TGZ-dGS) formation, followed by CYP3A4, CYP3A5, and CYP2C19. The involvement of CYP2C8 and CYP3A4 was confirmed with CYP form-selective chemical inhibitors. The impact of TGZ concentration on the rate of TGZ-dGS formation was also evaluated. In this instance, two distinctly different profiles were observed with recombinant CYP3A4 and CYP2C8. It is concluded that both CYP3A4/5 and CYP2C8 play a major role in the formation of TGZ adduct in HLM. However, the contribution of these CYPs varies depending on their relative expression and the concentration of TGZ.
Asunto(s)
Cromanos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Hipoglucemiantes/metabolismo , Microsomas Hepáticos/enzimología , Tiazolidinedionas/metabolismo , Hidrocarburo de Aril Hidroxilasas/metabolismo , Cromanos/administración & dosificación , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Compuestos de Dansilo/química , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica , Glutatión/química , Humanos , Hipoglucemiantes/administración & dosificación , Fenotipo , Compuestos de Sulfhidrilo/metabolismo , Tiazolidinedionas/administración & dosificación , TroglitazonaRESUMEN
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Indoles/síntesis química , Pirazinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT2 , Administración Oral , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Barrera Hematoencefálica/metabolismo , Línea Celular , Condicionamiento Operante , Conducta Alimentaria/efectos de los fármacos , Humanos , Indoles/química , Indoles/farmacología , Isoindoles , Masculino , Ratones , Necrosis , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/patología , Pirazinas/química , Pirazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Aumento de Peso/efectos de los fármacosRESUMEN
A sensitive and quantitative method was developed for the estimation of reactive metabolite formation in vitro. The method utilizes reduced glutathione (GSH) labeled with a fluorescence tag as a trapping agent and fluorescent detection for quantitation. The derivatization of GSH was accomplished by reaction of oxidized glutathione (GSSG) with dansyl chloride to form dansylated GSSG. Subsequent reduction of the disulfide bond yielded dansylated GSH (dGSH). Test compounds were incubated with human liver microsomes in the presence of dGSH and NADPH, and the resulting mixtures were analyzed by HPLC coupled with a fluorescence detector and a mass spectrometer for the quantitation and mass determination of the resulting dGSH adducts. The comparative chemical reactivity of dGSH vs GSH was investigated by monitoring the reaction of each with 1-chloro-2,4-dinitrobenzene or R-(+)-pulegone after bioactivation. dGSH was found to be equivalent to GSH in chemical reactivity toward both thiol reactive molecules. dGSH did not serve as a cofactor for glutathione S-transferase (GST)-mediated conjugation of 3,4-dichloronitrobenzene in incubations with either human liver S9 fractions or a recombinant GST, GSTM1-1. Reference compounds were tested in this assay, including seven compounds that have been reported to form GSH adducts along with seven drugs that are among the most prescribed in the current U.S. market and have not been reported to form GSH adducts. dGSH adducts were detected and quantitated in incubations with all seven positive reference compounds; however, there were no dGSH adducts observed with any of the widely prescribed drugs. In comparison with existing methods, this method is sensitive, quantitative, cost effective, and easy to implement.