Synthesis, in Silico and in Vitro Study on Phase I Metabolism of the Potent 5-Ht7/5-Ht1a/D2 Receptor Ligand: 4-Fluoron -(1-{2-[2-(Methylsulfanyl)- Phenoxy]Ethyl}Pyrrolidin-3-Yl) Benzene Sulfonamide
- Authors: Kubowicz-Kwaoeny P.1,2, Piska K.1,2, Klaoe K.1,2, Zmudzki P.3,4, Canale V.3,4, Zajdel P.3,4, Pêkala E.1,2
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Affiliations:
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College
- Aff2
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College
- Aff4
- Issue: Vol 53, No 8 (2019)
- Pages: 713-719
- Section: Article
- URL: https://journals.rcsi.science/0091-150X/article/view/245961
- DOI: https://doi.org/10.1007/s11094-019-02068-y
- ID: 245961
Cite item
Abstract
In the present study we analyze the synthesis as well as biotransformation pathways and metabolic stability of 4-fluoro- N -(1-{2-[2-(methylsulfanyl)phenoxy]ethyl}pyrrolidin-3-yl) benzene sulfonamide – thioether compound 5, with the affinity for several subtypes of the serotonin and dopamine receptor. Studies were conducted in vitro on liver microsomes from three species – mouse, rat, and human. The biotransformation was analyzed using liquid chromatography coupled with mass spectrometry. Two major metabolites (M1 and M2) – products of S-oxidation of the parent molecule – were generated both by in silico and in vitro methods. Use of three species allowed us to determine the interspecies differences in metabolic stability of tested compound. Two parameters, t0.5 and Clint , were calculated. Compound 5 was the most stable in human liver microsomes. Results are useful for understanding the interspecies differences in metabolism of the serotonin and dopamine receptor ligand associated with sulfur atom.
About the authors
Paulina Kubowicz-Kwaoeny
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff2
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street 30-688, Krakow
Kamil Piska
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff2
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street 30-688, Krakow
Katarzyna Klaoe
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff2
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street 30-688, Krakow
Pawe Zmudzki
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff4
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street, 30-688, Krakow
Vittorio Canale
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff4
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street, 30-688, Krakow
Pawel Zajdel
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff4
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street, 30-688, Krakow
Elźbieta Pêkala
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College; Aff2
Author for correspondence.
Email: elzbieta.pekala@uj.edu.pl
Poland, Cracow; 9 Medyczna Street 30-688, Krakow