RESUMO
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.
Assuntos
Aminas/química , Aminas/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Proteínas de Ligação a DNA/efeitos dos fármacos , Desenho de Fármacos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Cristalografia por Raios X , Receptores X do Fígado , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Receptores Nucleares Órfãos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Sítios de Ligação , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Compostos de Anilina/química , Etanolamina/química , Etanolamina/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Animais , Glicemia/metabolismo , Linhagem Celular , Cricetinae , AMP Cíclico/metabolismo , Cães , Etanolamina/síntese química , Glicosilação/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores de Estrogênio/efeitos dos fármacos , Tamoxifeno , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Receptor alfa de Estrogênio/efeitos dos fármacos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tamoxifeno/análogos & derivados , Tamoxifeno/síntese química , Tamoxifeno/farmacologiaRESUMO
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.
Assuntos
Receptor beta de Estrogênio/agonistas , Hidrazinas/síntese química , Fenóis/síntese química , Receptores de Estrogênio/agonistas , Ligação Competitiva , Receptor beta de Estrogênio/genética , Transferência Ressonante de Energia de Fluorescência , Genes Reporter , Células HeLa , Proteínas de Choque Térmico/biossíntese , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Ligantes , Mimetismo Molecular , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fenóis/química , Fenóis/farmacologia , Receptores de Estrogênio/genética , Relação Estrutura-Atividade , Fatores de Transcrição/biossínteseRESUMO
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.