Two Novel Metformin Carboxylate Salts and the Accidental Discovery of Two 1,3,5-Triazine Antihyperglycemic Agent
© 2023 The Authors. Published by American Chemical Society..
Metformin (MET), commonly marketed as a hydrochloride salt (MET-HCl) for better pharmacokinetic profile over the free base, would release a high concentration of chloride ions and cause adverse gastrointestinal effects. The preparation of chloride-free MET salts could potentially circumvent this issue. In this study, seven carboxylic acids (formic acid, acetic acid, malonic acid, succinic acid, fumaric acid, cinnamic acid, and acetylsalicylic acid) were used for preparing MET carboxylate salts. When compared with MET-HCl, all MET salts/salt hydrates show lower dissolution rates in pH 6.8 phosphate buffer. However, the cinnamic acid and acetylsalicylic acid show significantly higher dissolution rates in the forms of MET salt/salt hydrate. In the permeability test, the permeability of the MET in all of the salts was not improved. However, the permeability of cinnamic acid in the MET cinnamate is reduced, and the permeability of acetylsalicylic acid in the MET acetylsalicylate is increased. Meanwhile, at a higher crystallization temperature, the acetone solvent and a hydrolyzed product of acetylsalicylic acid react with MET respectively, leading to two unexpected 1,3,5-triazine derivatives. The results of in vitro bioactivity assays indicate that one of the triazine molecules promote glucose consumption more effectively than MET-HCl, and had relatively weak lactate production ability at low concentration. This glucose metabolism regulating compound may serve as a novel lead antihyperglycemic agent for further optimization.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
ACS omega - 8(2023), 50 vom: 19. Dez., Seite 48028-48041 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
An, Qi [VerfasserIn] |
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| Links: |
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| Themen: |
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| Anmerkungen: |
Date Revised 25.12.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/acsomega.3c06721 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM366347918 |
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| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 The Authors. Published by American Chemical Society. | ||
| 520 | |a Metformin (MET), commonly marketed as a hydrochloride salt (MET-HCl) for better pharmacokinetic profile over the free base, would release a high concentration of chloride ions and cause adverse gastrointestinal effects. The preparation of chloride-free MET salts could potentially circumvent this issue. In this study, seven carboxylic acids (formic acid, acetic acid, malonic acid, succinic acid, fumaric acid, cinnamic acid, and acetylsalicylic acid) were used for preparing MET carboxylate salts. When compared with MET-HCl, all MET salts/salt hydrates show lower dissolution rates in pH 6.8 phosphate buffer. However, the cinnamic acid and acetylsalicylic acid show significantly higher dissolution rates in the forms of MET salt/salt hydrate. In the permeability test, the permeability of the MET in all of the salts was not improved. However, the permeability of cinnamic acid in the MET cinnamate is reduced, and the permeability of acetylsalicylic acid in the MET acetylsalicylate is increased. Meanwhile, at a higher crystallization temperature, the acetone solvent and a hydrolyzed product of acetylsalicylic acid react with MET respectively, leading to two unexpected 1,3,5-triazine derivatives. The results of in vitro bioactivity assays indicate that one of the triazine molecules promote glucose consumption more effectively than MET-HCl, and had relatively weak lactate production ability at low concentration. This glucose metabolism regulating compound may serve as a novel lead antihyperglycemic agent for further optimization | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Li, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Zhehui |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Nuoqi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xueying |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xiuying |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Dezhi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Guanhua |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, H C Stephen |e verfasserin |4 aut | |
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