RESUMEN
We disclosed a novel series of G-protein coupled receptor 119 (GPR119) agonists based on a bicyclic amine scaffold. Through the optimization of hit compound 1, we discovered that the basic nitrogen atom of bicyclic amine played an important role in GPR119 agonist activity expression and that an indanone in various bicyclic rings was suitable in this series of compounds. The indanone derivative 2 showed the effect of plasma glucose control in oGTT and scGTT in the rodent model.
Asunto(s)
Aminas/química , Compuestos Bicíclicos con Puentes/química , Hipoglucemiantes/síntesis química , Indanos/síntesis química , Pirimidinas/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Aminas/síntesis química , Aminas/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Indanos/química , Indanos/farmacología , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
Human ABCG subfamily proteins ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8 are half-type ATP-binding cassette (ABC) proteins that transport sterols or xenobiotics. ABCG1, ABCG2, and ABCG4 function as homodimers on the plasma membrane. In contrast, ABCG5 and ABCG8 function as heterodimers on the plasma membrane, and the homodimer of either ABCG5 or ABCG8 is retained in the endoplasmic reticulum (ER). To examine the molecular mechanisms of the regulated trafficking of ABCG5 and ABCG8, the subcellular localizations of chimeric proteins, fused with ABCG1 or ABCG2, were analyzed. Homodimers of chimeric proteins, in which the N-terminal cytosolic domain of ABCG1 or ABCG2 was fused to the C-terminal transmembrane domain of ABCG5 or ABCG8 localized to the plasma membrane, whereas chimeric proteins in which the N-terminal cytosolic domain of ABCG5 or ABCG8 was fused to the C-terminal transmembrane domain of ABCG1 or ABCG2 localized to the ER. Mutations in ER-retrieval motif-like sequences in ABCG5 or ABCG8 did not affect their subcellular localization. This suggests that the N-terminal cytosolic domains of ABCG5 and ABCG8 are involved in ER retention of their homodimers, and that novel ER-retention or -retrieval motifs exist within these domains.
