Abstract
BackgroundThe 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.MethodsStructures 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.ResultsFor (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.Graphic abstract
Highlights
Among the ADME properties, metabolites’ identification constitutes an important paradigm in the early phase of drug discovery and development [1]
Due to the ever-increasing quantity of new chemical entities (NCEs)’ fast, reliable and high-throughput screening techniques, e.g., high-resolution mass spectrometry (HRMS) and electrochemical mimicry play an essential role in the process of evaluation of new drug candidates allowing the elimination of many compounds at the early stages of the drug discovery and limiting the costs of the new drug development [4]
The stability of the parent compound in stock and working solutions and in vitro in rat serum was investigated before the identification of metabolites
Summary
Among the ADME (absorption, distribution, metabolism, and excretion) properties, metabolites’ identification constitutes an important paradigm in the early phase of drug discovery and development [1]. Due to the ever-increasing quantity of NCEs’ fast, reliable and high-throughput screening techniques, e.g., high-resolution mass spectrometry (HRMS) and electrochemical mimicry play an essential role in the process of evaluation of new drug candidates allowing the elimination of many compounds at the early stages of the drug discovery and limiting the costs of the new drug development [4]. Identification studies of predicted metabolites were made by a high-resolution mass spectrometer LTQ XL Orbitrap Discovery and using a R oxyTM system, for online electrochemical mimicry of oxidative metabolism by cytochrome P450s connected to QTRAP 5500. Conclusion (RS)-9 was extensively metabolised to several phase I and II metabolites, and renal excretion was a minor route in its elimination
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