Sakairi M, Kogami M, Torii M, Kuno Y, Ohsawa Y, Makino M, Kataoka D, Okamoto R, Miyazawa T, Inoue M, Takahashi N, Harada S, Watanabe N
Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Hokusei-cho, Inabe, Mie, Japan.
Arzneimittelforschung. 2012 Nov;62(11):537-44. doi: 10.1055/s-0032-1323760. Epub 2012 Sep 12.
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.
G蛋白偶联受体119（GPCR 119，即GPR119）激动剂作为治疗2型糖尿病的一种有前景的治疗选择，已受到广泛关注。GPR119是胰岛β细胞中表达的GPCR之一，其激活以葡萄糖依赖的方式增强胰岛素分泌的刺激作用。我们最近报道了一系列6-氨基-1H-茚-1-酮类化合物，它们是强效、选择性且口服生物可利用的GPR119激动剂，其氨基不仅在其类药物性质（如高水溶性）中起重要作用，而且在其强效激动活性中也起重要作用。然而，这些化合物中的许多对人类醚-à-去相关基因通道表现出强至中度抑制作用。通过用缺电子杂芳环取代相邻苯环来减弱氨基的碱性，得到了几个杂环核心，其中6-氨基呋咱并[3,2-c]吡啶-3(2H)-酮被选为一个有前景的骨架。围绕侧链部分的进一步优化导致了17i的发现，它不仅表现出强大的人类GPR119激动活性（EC50 = 14 nM），而且对小鼠胃排空和血浆总胰高血糖素样肽-1水平有有益影响。
