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Design and biological evaluation of tetrahydropyridine derivatives as novel human GPR119 agonists
Institution:1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China;2. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, PR China;3. College of Pharmacy, Liaocheng University, Liaocheng 252059, PR China;4. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China;5. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China;1. National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China;2. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China;1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China;2. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China;3. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China;4. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China;1. Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea;2. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;1. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China;2. National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China
Abstract:A series of novel tetrahydropyridine derivatives were prepared and evaluated using cell-based measurements. Systematic optimization of general structure G-1 led to the identification of compound 35 (EC50 = 4.9 nM) and 37 (EC50 = 8.8 nM) with high GPR119 agonism activity and moderate clog P. Through single and long-term pharmacodynamic experiments, we found that compound 35 showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment.
Keywords:Type 2 diabetes  GPR119 agonist  1  2  3  6-Tetrahydropyridine derivatives  OGTT
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