Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes
GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/22/6907 |
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| author | Guoxia Ji Qinghua Guo Qidi Xue Ruifang Kong Shiben Wang Kang Lei Renmin Liu Xuekun Wang |
| author_facet | Guoxia Ji Qinghua Guo Qidi Xue Ruifang Kong Shiben Wang Kang Lei Renmin Liu Xuekun Wang |
| author_sort | Guoxia Ji |
| collection | DOAJ |
| description | GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound <b>11b</b> showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, <b>11b</b> showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound <b>11b</b> could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound <b>11b</b> might be a promising drug candidate for the treatment of T2DM. |
| first_indexed | 2024-03-10T05:14:05Z |
| format | Article |
| id | doaj.art-63131e8f92c846e99c5f3dfc66a20761 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:14:05Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-63131e8f92c846e99c5f3dfc66a207612023-11-23T00:35:32ZengMDPI AGMolecules1420-30492021-11-012622690710.3390/molecules26226907Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 DiabetesGuoxia Ji0Qinghua Guo1Qidi Xue2Ruifang Kong3Shiben Wang4Kang Lei5Renmin Liu6Xuekun Wang7School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaSchool of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng 252059, ChinaGPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound <b>11b</b> showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, <b>11b</b> showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound <b>11b</b> could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound <b>11b</b> might be a promising drug candidate for the treatment of T2DM.https://www.mdpi.com/1420-3049/26/22/6907GPR120synthesistype 2 diabetespharmacokinetic profiles |
| spellingShingle | Guoxia Ji Qinghua Guo Qidi Xue Ruifang Kong Shiben Wang Kang Lei Renmin Liu Xuekun Wang Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes Molecules GPR120 synthesis type 2 diabetes pharmacokinetic profiles |
| title | Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes |
| title_full | Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes |
| title_fullStr | Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes |
| title_full_unstemmed | Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes |
| title_short | Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes |
| title_sort | novel gpr120 agonists with improved pharmacokinetic profiles for the treatment of type 2 diabetes |
| topic | GPR120 synthesis type 2 diabetes pharmacokinetic profiles |
| url | https://www.mdpi.com/1420-3049/26/22/6907 |
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