RESUMEN
A cocrystal structure of T1317 (3) bound to hLXRbeta was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 ( 20) as a high-affinity LXRbeta ligand (IC 50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRbeta reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.
Asunto(s)
Aminas/química , Aminas/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Proteínas de Unión al ADN/efectos de los fármacos , Diseño de Fármacos , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Cristalografía por Rayos X , Receptores X del Hígado , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Estructura Molecular , Receptores Nucleares Huérfanos , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a novel series of heterobiaryl phenethanolamine beta3 adrenergic receptor agonists are described. The furan analogue 49 was shown to elicit a significant dose-dependent lowering of plasma glucose in a rodent model of type 2 diabetes.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Sitios de Unión , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Compuestos de Anilina/química , Etanolamina/química , Etanolamina/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Animales , Glucemia/metabolismo , Línea Celular , Cricetinae , AMP Cíclico/metabolismo , Perros , Etanolamina/síntesis química , Glicosilación/efectos de los fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores de Estrógenos/efectos de los fármacos , Tamoxifeno , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Receptor alfa de Estrógeno/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tamoxifeno/análogos & derivados , Tamoxifeno/síntesis química , Tamoxifeno/farmacologíaRESUMEN
The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.
Asunto(s)
Receptor beta de Estrógeno/agonistas , Hidrazinas/síntesis química , Fenoles/síntesis química , Receptores de Estrógenos/agonistas , Unión Competitiva , Receptor beta de Estrógeno/genética , Transferencia Resonante de Energía de Fluorescencia , Genes Reporteros , Células HeLa , Proteínas de Choque Térmico/biosíntesis , Humanos , Hidrazinas/química , Hidrazinas/farmacología , Ligandos , Imitación Molecular , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenoles/química , Fenoles/farmacología , Receptores de Estrógenos/genética , Relación Estructura-Actividad , Factores de Transcripción/biosíntesisRESUMEN
A solid-phase synthesis of substituted benzopyranoisoxazoles is described. The six-step synthesis features a novel method of generating nitrile oxides on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne for assembly of the benzopyranoisoxazole scaffold. Furthermore, the utilization of single-bead attenuated total reflectance Fourier transform infrared (ATR-IR) microspectroscopy as an essential analytical tool for reaction optimization is highlighted.
