RESUMEN
3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral µ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the µ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.
Asunto(s)
Antipruriginosos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Hexanos/síntesis química , Prurito/tratamiento farmacológico , Receptores Opioides mu/antagonistas & inhibidores , Animales , Antipruriginosos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Perros , Cobayas , Hexanos/farmacología , Humanos , Técnicas In Vitro , Cinética , Ligandos , Prurito/metabolismo , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.