Discovery and biological evaluation of novel 4-amino-2-phenylpyrimidine derivatives as potent and orally active GPR119 agonists
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- 作者：Kenji Negoro ; Yasuhiro Yonetoku ; Hana Misawa-Mukai ; Wataru Hamaguchi ; Tatsuya Maruyama ; Shigeru Yoshida ; Makoto Takeuchi ; Mitsuaki Ohta
- 关键词：Type 2 diabetes mellitus ; Glucose-dependent insulin secretion ; G-protein-coupled receptor 119 ; GPR119 agonist
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2012
- 出版时间：1 September, 2012
- 年：2012
- 卷：20
- 期：17
- 页码：5235-5246
- 全文大小：750 K
文摘
Novel 4-amino-2-phenylpyrimidine derivatives were synthesized and evaluated as GPR119 agonists. Optimization of the substituents on the phenyl ring at the 2-position and the amino group at the 4-position led to the identification of 3,4-dihalogenated and 2,4,5-trihalogenated phenyl derivatives showing potent GPR119 agonistic activity. The advanced analog (2R)-3-{[2-(4-chloro-2,5-difluorophenyl)-6-ethylpyrimidin-4-yl]amino}propane-1,2-diol (24g) was found to improve glucose tolerance at 1 mg/kg po in mice and to show excellent pharmacokinetic profiles in mice and monkeys. Compound 24g also showed an excellent antidiabetic effect in diabetic kk/Ay mice after one week of single daily treatment. These results demonstrate that novel GPR119 agonist 24g improves glucose tolerance not only by enhancing glucose-dependent insulin secretion but also by preserving pancreatic ¦Â-cell function.