Synthesis and preclinical pharmacokinetic study of DHA‐10, a novel potential antifungal pogostone analogue
Objectives The emergence of fungal disease calls for the urgency of development of novel drug. In this study, we developed a novel pogostone analogue, DHA-10 and investigated its preclinical pharmacokinetics, tissue distribution, excretion and protein binding rate in rats. Methods DHA-10 was synthesized with dehydroacetic acid (DHA) as the starting material and the structure confirmed by NMR and HRMS. The LC-MS/MS was applied to quantitative analysis of DHA-10 concentrations in the biological samples. Key finding DHA-10 was eliminated rapidly in rat plasma with half-lives of 3.39 ± 0.5, 3.24 ± 0.32 and 3.80 ± 0.40 h after single oral doses of 70, 140 and 280 mg/kg, respectively, and showed linear pharmacokinetic within the examined dosage range. The oral bioavailability of DHA-10 was 69.09 ± 3.9%. DHA-10 distributed widely in tissues with highest tissue concentration was found in small intestine at 2.5 h postdose, followed by the stomach, liver and uterus. Approximately, 1.50 ± 0.26% and 9.12 ± 2.53% of parent drug was excreted via the urine and faeces within 48 h, respectively; 1.45 ± 0.12% was excreted into the bile up to 36 h after a single oral administration of 140 mg/kg. Binding rate of DHA-10 with plasma protein was about 78.80 ± 1.75% in a concentration-independent manner. Conclusions DHA-10 was successfully synthesized and characterized. The preclinical pharmacokinetics study in rats supported the further development of this new antifungal candidate compound..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:69 |
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| Enthalten in: |
Journal of pharmacy and pharmacology - 69(2017), 9, Seite 1084-1090 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Ming [VerfasserIn] |
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| Links: |
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| doi: |
10.1111/jphp.12750 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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OLC1996934295 |
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| 245 | 1 | 0 | |a Synthesis and preclinical pharmacokinetic study of DHA‐10, a novel potential antifungal pogostone analogue |
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| 520 | |a Objectives The emergence of fungal disease calls for the urgency of development of novel drug. In this study, we developed a novel pogostone analogue, DHA-10 and investigated its preclinical pharmacokinetics, tissue distribution, excretion and protein binding rate in rats. Methods DHA-10 was synthesized with dehydroacetic acid (DHA) as the starting material and the structure confirmed by NMR and HRMS. The LC-MS/MS was applied to quantitative analysis of DHA-10 concentrations in the biological samples. Key finding DHA-10 was eliminated rapidly in rat plasma with half-lives of 3.39 ± 0.5, 3.24 ± 0.32 and 3.80 ± 0.40 h after single oral doses of 70, 140 and 280 mg/kg, respectively, and showed linear pharmacokinetic within the examined dosage range. The oral bioavailability of DHA-10 was 69.09 ± 3.9%. DHA-10 distributed widely in tissues with highest tissue concentration was found in small intestine at 2.5 h postdose, followed by the stomach, liver and uterus. Approximately, 1.50 ± 0.26% and 9.12 ± 2.53% of parent drug was excreted via the urine and faeces within 48 h, respectively; 1.45 ± 0.12% was excreted into the bile up to 36 h after a single oral administration of 140 mg/kg. Binding rate of DHA-10 with plasma protein was about 78.80 ± 1.75% in a concentration-independent manner. Conclusions DHA-10 was successfully synthesized and characterized. The preclinical pharmacokinetics study in rats supported the further development of this new antifungal candidate compound. | ||
| 540 | |a Nutzungsrecht: © 2017 Royal Pharmaceutical Society | ||
| 650 | 4 | |a pogostone analogue | |
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| 650 | 4 | |a Tissues | |
| 650 | 4 | |a Pharmacology | |
| 650 | 4 | |a Biological samples | |
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| 650 | 4 | |a Small intestine | |
| 650 | 4 | |a Rats | |
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| 650 | 4 | |a Analogue | |
| 650 | 4 | |a Synthesis | |
| 650 | 4 | |a Binding | |
| 650 | 4 | |a Rodents | |
| 650 | 4 | |a Uterus | |
| 650 | 4 | |a Fungi | |
| 650 | 4 | |a Quantitative analysis | |
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| 650 | 4 | |a Biological properties | |
| 650 | 4 | |a Pharmacokinetics | |
| 650 | 4 | |a Urine | |
| 650 | 4 | |a Bile | |
| 650 | 4 | |a Fungicides | |
| 650 | 4 | |a Dosage | |
| 650 | 4 | |a Liver | |
| 650 | 4 | |a Excretion | |
| 650 | 4 | |a Nuclear magnetic resonance | |
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| 700 | 1 | |a Zhou, Yanfen |4 oth | |
| 700 | 1 | |a Zhu, Jianwei |4 oth | |
| 700 | 1 | |a Ma, Bo |4 oth | |
| 700 | 1 | |a Fang, Zheng |4 oth | |
| 700 | 1 | |a Zhang, Qi |4 oth | |
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