Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim..
Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
ChemMedChem - 15(2020), 16 vom: 19. Aug., Seite 1608-1617 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zeng, Shaogao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.06.2021 Date Revised 14.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cmdc.202000175 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy | ||
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| 650 | 7 | |a DPP4 protein, human |2 NLM | |
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| 700 | 1 | |a Dou, Wenyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Manna |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Jiehuang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qiaoli |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Wenhui |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yanfang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Hui |e verfasserin |4 aut | |
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