RESUMO
The combination of SmI2 and the conjugate base of triethylurea (TEU-) has been shown to favor the cyclization of unsaturated halides over direct reduction to a much greater extent than other SmI2-based reductants. Aryl, heteroaryl, and alkyl halides (X = Br, Cl, F) readily undergo heterocyclization and carbocyclization in the presence of SmI2/TEU-.
RESUMO
We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
Assuntos
Dor Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Receptor trkA/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/química , Indóis/farmacocinética , Ligantes , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacocinética , Ureia/análogos & derivados , Ureia/química , Ureia/farmacocinéticaRESUMO
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Assuntos
Analgésicos/química , Piridinas/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Adjuvante de Freund/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Piridinas/síntese química , Piridinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismoRESUMO
Activation of liver X receptors (LXRs) induces reverse cholesterol transport and increases high-density lipoprotein cholesterol in vivo. Here, we describe novel, functional, homogeneous cell-based fluorescence resonance energy transfer assays for identifying agonists of LXRs using beta-lactamase as the reporter gene. Stable Chinese hamster ovary cell lines expressing LXRalpha-GAL4 or LXRbeta-GAL4 fusion proteins that regulate beta-lactamase transcription from upstream 7 x UAS GAL4 DNA binding sequences were generated and characterized. Synthetic and natural ligands of LXR dose-dependently activated the expression of beta-lactamase in a subtype-specific manner. These assays were used to demonstrate that a 1-pyridyl hydantoin small molecule LXR synthetic ligand specifically activates LXRalpha receptors. The beta-lactamase assays were optimized for cell density, dimethyl sulfoxide sensitivity, and time of agonist stimulation. Clonal LXRbeta-GAL4-beta-lactamase cells were miniaturized into an ultra high throughput (3456-well nanoplates) screening format.