RESUMEN
New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.
Asunto(s)
Niacinamida/análogos & derivados , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Regulación del Apetito/efectos de los fármacos , Diseño de Fármacos , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Niacinamida/química , Niacinamida/farmacología , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Ratas , Relación Estructura-ActividadRESUMEN
A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.
Asunto(s)
Fármacos Antiobesidad/química , Receptores de Ghrelina/agonistas , Administración Oral , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/farmacocinética , Modelos Animales de Enfermedad , Agonismo Inverso de Drogas , Semivida , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Niacinamida/administración & dosificación , Niacinamida/química , Niacinamida/farmacocinética , Obesidad/tratamiento farmacológico , Obesidad/patología , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadRESUMEN
Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.
Asunto(s)
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacología , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Citocromo P-450 CYP3A/metabolismo , Agonismo Inverso de Drogas , Receptores de Ghrelina/agonistas , 6-Aminonicotinamida/metabolismo , Fármacos Antiobesidad/metabolismo , Descubrimiento de Drogas , Humanos , Microsomas Hepáticos/metabolismo , Obesidad/tratamiento farmacológico , Receptores de Ghrelina/metabolismoRESUMEN
A series of truncated analogs of α-galactosylceramide with altered ceramide moiety was prepared, and evaluated for Th2-biased response in the context of IL-4/IFN-γ ratio. Phytosphingosine-modified analogs including cyclic, aromatic and ethereal compounds as well as the C-glycoside analog of OCH (2) with their cytokine inducing profile are disclosed.
Asunto(s)
Galactosilceramidas/química , Galactosilceramidas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Animales , Antígenos CD1d/química , Antígenos CD1d/metabolismo , Sitios de Unión , Simulación por Computador , Galactosilceramidas/síntesis química , Ratones , Ratones Endogámicos C57BL , Células Th2/efectos de los fármacosRESUMEN
Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.
Asunto(s)
2-Naftilamina/análogos & derivados , Pirimidinas/síntesis química , Receptores de Ácido Retinoico/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , 2-Naftilamina/síntesis química , 2-Naftilamina/química , 2-Naftilamina/farmacología , Benzoatos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Diferenciación Celular/efectos de los fármacos , Depresión Química , Dimerización , Células HL-60 , Humanos , Pirimidinas/química , Pirimidinas/farmacología , Receptores X Retinoide , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacologíaRESUMEN
Analogs of immunomodulatory glycolipid OCH (2) were prepared and minimum structure requirement to exhibit equivalent profiles was disclosed. Analogs bearing non-linear hydrocarbon chain in the phytosphingosine moiety (18, 19) were shown for the first time to possess comparable cytokine inducing profile to 2. Molecular modeling of 2/hCD1d complex based on the crystal structure of alpha-GalCer (1)/hCD1d complex is also described.
Asunto(s)
Citocinas/metabolismo , Glucolípidos/metabolismo , Factores Inmunológicos/metabolismo , Esfingosina/análogos & derivados , Células Th2/metabolismo , Animales , Humanos , Estructura Molecular , Esfingosina/químicaRESUMEN
[reaction: see text] A practical and efficient total synthesis of (2S,3S,4R)-1-O-(alpha-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonanetriol, OCH 1b, a potential therapeutic candidate for Th1-mediated autoimmune diseases, is described. The synthesis incorporates direct alkylation onto epoxide 5 and stereospecific halide ion catalyzed alpha-glycosidation reaction. A key intermediate 10 was obtained in only eight steps and 37% overall yield from commercially available d-arabitol 2, and the total synthesis of 1b was accomplished in 12 steps and 19% overall yield. This method will enable the synthesis of a variety of phytosphingolipids, especially that with the shorter sphingosine side chain than 1a, in a highly stereoselective manner.