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一种具有β肾上腺素能活性的新型化合物的初步代谢产物鉴定。

A preliminary metabolites identification of a novel compound with β-adrenolytic activity.

机构信息

Chair and Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.

Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Bobrzynskiego 14, 30-348, Krakow, Poland.

出版信息

Pharmacol Rep. 2021 Oct;73(5):1373-1389. doi: 10.1007/s43440-021-00273-9. Epub 2021 May 29.

DOI:10.1007/s43440-021-00273-9
PMID:34050907
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8163589/
Abstract

BACKGROUND

The identification of main metabolites and assessment of renal excretion of a novel compound with β-adrenolytic activity (2RS)-1-(1H-indol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol, briefly called (RS)-9 or 2F109, were studied in vivo in rat serum, urine, faeces, liver, intestine, lungs and kidneys, and in vitro in rat liver microsomes.

METHODS

Structures of the metabolites have been developed by comparing the high-resolution product ion mass spectra of metabolites and the parent compound based on the differences in mass values of main fragments. Quantitative analysis of (RS)-9 was done using a system of liquid chromatography coupled with a triple quadrupole mass spectrometer API 2000. Identification studies of predicted metabolites were made by a high-resolution mass spectrometer LTQ XL Orbitrap Discovery and using a Roxy system, for online electrochemical mimicry of oxidative metabolism by cytochrome P450s connected to QTRAP 5500.

RESULTS

For (RS)-9 (m/z 357.2084) phase I metabolites derived from oxidation process: hydroxyl derivatives (m/z 373.2470) and dihydroxyl derivatives (m/z 389.4318), and phase II metabolites: N-methylated compound (m/z 371.1612), O-glucuronide (m/z 533.5118), and sulfate (m/z 437.2350) were identified.

CONCLUSION

(RS)-9 was extensively metabolised to several phase I and II metabolites, and renal excretion was a minor route in its elimination.

摘要

背景

具有β-肾上腺素能阻滞活性的新型化合物（2RS）-1-（1H-吲哚-4-氧基）-3-（（2-（2-甲氧基苯氧基）乙基）氨基）-2-丙醇（简称（RS）-9 或 2F109）的主要代谢产物的鉴定和肾脏排泄的评估在大鼠血清、尿液、粪便、肝脏、肠道、肺和肾脏中进行了体内研究，并在大鼠肝微粒体中进行了体外研究。

方法

根据主要片段的质量值差异，通过比较代谢产物和母体化合物的高分辨率产物离子质谱，推断出代谢产物的结构。使用液相色谱-三重四极杆质谱联用 API 2000 系统对（RS）-9 进行定量分析。使用高分辨率质谱 LTQ XL Orbitrap Discovery 和 Roxy 系统对预测代谢产物进行鉴定研究，通过连接到 QTRAP 5500 的细胞色素 P450 模拟在线电化学氧化代谢。

结果

对于（RS）-9（m/z 357.2084）的 I 相代谢产物来源于氧化过程：羟基衍生物（m/z 373.2470）和二羟基衍生物（m/z 389.4318），以及 II 相代谢产物：N-甲基化化合物（m/z 371.1612）、O-葡糖苷酸（m/z 533.5118）和硫酸盐（m/z 437.2350）。

结论

（RS）-9 被广泛代谢为几种 I 相和 II 相代谢产物，肾脏排泄是其消除的次要途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/cffdf8acbc9f/43440_2021_273_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/401d6934b2fb/43440_2021_273_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/944384c903a8/43440_2021_273_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/c18622b69740/43440_2021_273_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/4955f1f6949d/43440_2021_273_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/9321fb625839/43440_2021_273_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/a523f1da9e4e/43440_2021_273_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/ff97167aa53e/43440_2021_273_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/8c1526a06533/43440_2021_273_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/cffdf8acbc9f/43440_2021_273_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/401d6934b2fb/43440_2021_273_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/944384c903a8/43440_2021_273_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/c18622b69740/43440_2021_273_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/4955f1f6949d/43440_2021_273_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/9321fb625839/43440_2021_273_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/a523f1da9e4e/43440_2021_273_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/ff97167aa53e/43440_2021_273_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/8c1526a06533/43440_2021_273_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/820f/8460495/cffdf8acbc9f/43440_2021_273_Fig8_HTML.jpg

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