Synthesis and Biological Evaluation of a 6-Aminofuro[3,2–c]pyridin-3(2H)-one Series of GPR 119 Agonists

Abstract

G protein-coupled receptor 119 (GPCR 119 (GPR119)) agonists have received considerable attention as a promising therapeutic option for treatment of type 2 diabetes mellitus. GPR119 is one of the GPCRs expressed in pancreatic islet β-cells and its activation enhances stimulation of insulin secretion in a glucose-dependent manner. We have recently described a series of 6-amino-1H-indan-1-ones as potent, selective, and orally bioavailable GPR119 agonists with an amino group that plays important roles not only in their drug-like properties, such as high aqueous solubility, but also in their potent agonistic activity. However, many of these compounds displayed strong to moderate inhibition of human ether-à-go-go related gene channel. Attenuation of the basicity of the amino group by replacing the adjacent benzene ring with electron-deficient heteroaromatic rings provided several heterocyclic cores among which 6-aminofuro[3,2–c]pyridin-3(2H)-one was selected as a promising scaffold. Further optimization around the side chain moiety led to the discovery of 17i, which showed not only strong human GPR119 agonistic activity (EC₅₀=14 nM), but also beneficial effects on gastric emptying and plasma total glucagon-like peptide-1 levels in mice.

Key words

human ether-à-go-go related gene channel inhibition - 6-aminofuro[3,2-c]pyridin-3(2H)-one - gastric emptying - glucagon-like peptide-1

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