title: 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.
authors.affiliation: Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Hokusei-cho, Inabe, Mie, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakairi
authors.forename: M
authors.initials: M
authors.lastname: Kogami
authors.forename: M
authors.initials: M
authors.lastname: Torii
authors.forename: Y
authors.initials: Y
authors.lastname: Kuno
authors.forename: Y
authors.initials: Y
authors.lastname: Ohsawa
authors.forename: M
authors.initials: M
authors.lastname: Makino
authors.forename: D
authors.initials: D
authors.lastname: Kataoka
authors.forename: R
authors.initials: R
authors.lastname: Okamoto
authors.forename: T
authors.initials: T
authors.lastname: Miyazawa
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: S
authors.initials: S
authors.lastname: Harada
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D005746:Gastric Emptying / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D011728:Pyridones; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1