Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4

Andrzej Chodkowski; Martyna Z Wróbel; Jadwiga Turło; Jerzy Kleps; Agata Siwek; Gabriel Nowak; Mariusz Belka; Tomasz Bączek; Aleksander P Mazurek; Franciszek Herold

doi:10.1016/j.ejmech.2014.10.069

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4

Eur J Med Chem. 2015 Jan 27:90:21-32. doi: 10.1016/j.ejmech.2014.10.069. Epub 2014 Oct 24.

Authors

Affiliations

¹ Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland.
² Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland. Electronic address: [email protected].
³ Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
⁴ Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy with Subfaculty of Laboratory Medicine, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland.
⁶ Department of Drug Chemistry, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland; National Medicines Institute, 30/34 Chełmska Street, 00-725 Warszawa, Poland.
⁷ Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland. Electronic address: [email protected].

PMID: 25461308
DOI: 10.1016/j.ejmech.2014.10.069

Abstract

This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.

Keywords: ADME; Antidepressants; Dual 5-HT(1A)/SERT activity; Pyrido[1,2-c]pyrimidines.

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Serotonin, 5-HT1A / metabolism*
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Pyrimidines
Serotonin Uptake Inhibitors
octahydropyrido(1,2-c)pyrimidine
Receptor, Serotonin, 5-HT1A