ABSTRACT
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.
Subject(s)
Amines/chemistry , Amines/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , DNA-Binding Proteins/drug effects , Drug Design , Receptors, Cytoplasmic and Nuclear/drug effects , Crystallography, X-Ray , Liver X Receptors , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Molecular Structure , Orphan Nuclear Receptors , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Binding Sites , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Aniline Compounds/chemistry , Ethanolamine/chemistry , Ethanolamine/pharmacology , Receptors, Adrenergic, beta-3/metabolism , Animals , Blood Glucose/metabolism , Cell Line , Cricetinae , Cyclic AMP/metabolism , Dogs , Ethanolamine/chemical synthesis , Glycosylation/drug effects , Hemoglobins/metabolism , Humans , Male , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Receptors, Cytoplasmic and Nuclear/drug effects , Receptors, Estrogen/drug effects , Tamoxifen , Binding Sites/drug effects , Crystallography, X-Ray , Drug Design , Estrogen Receptor alpha/drug effects , Humans , Ligands , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tamoxifen/analogs & derivatives , Tamoxifen/chemical synthesis , Tamoxifen/pharmacologyABSTRACT
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.
Subject(s)
Estrogen Receptor beta/agonists , Hydrazines/chemical synthesis , Phenols/chemical synthesis , Receptors, Estrogen/agonists , Binding, Competitive , Estrogen Receptor beta/genetics , Fluorescence Resonance Energy Transfer , Genes, Reporter , HeLa Cells , Heat-Shock Proteins/biosynthesis , Humans , Hydrazines/chemistry , Hydrazines/pharmacology , Ligands , Molecular Mimicry , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phenols/chemistry , Phenols/pharmacology , Receptors, Estrogen/genetics , Structure-Activity Relationship , Transcription Factors/biosynthesisABSTRACT
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.
