RESUMEN
Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.
Asunto(s)
Glicósidos/química , Hipoglucemiantes/química , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Compuestos de Espiro/química , Animales , Ciclización , Glicósidos/síntesis química , Glicósidos/farmacocinética , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Transportador 2 de Sodio-Glucosa/metabolismoRESUMEN
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Asunto(s)
Aminas/síntesis química , Aminoácidos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácido gamma-Aminobutírico/síntesis química , Aminas/química , Aminas/farmacocinética , Aminoácidos/química , Aminoácidos/farmacocinética , Animales , Barrera Hematoencefálica/metabolismo , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Células CHO , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Gabapentina , Neuralgia/tratamiento farmacológico , Dimensión del Dolor , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
