RESUMO
Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.
Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Cálcio/metabolismo , Ciclobutanos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Conformação Molecular , Piridinas/química , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.
