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Tricyclic xanthine derivatives containing a basic substituent: adenosine receptor affinity and drug-related properties

Abstract

A library of 27 novel amide derivatives of annelated xanthines was designed and synthesized. The new compounds represent 1,3-dipropyl- and 1,3-dibutyl-pyrimido[2,1-f]purinedione-9-ethylphenoxy derivatives including a CH2CONH linker between (CH2)2-amino group and the phenoxy moiety. A synthetic strategy to obtain the final products was developed involving solvent-free microwave irradiation. The new compounds were evaluated for their adenosine receptor (AR) affinities. The most potent derivatives contained a terminal tertiary amino function. Compounds with nanomolar AR affinities and at the same time high water-solubility were obtained (A1 (Ki = 24 - 605 nM), A2A (Ki = 242 - 1250 nM), A2B (Ki = 66 - 911 nM) and A3 (Ki = 155 - 1000 nM)). 2-(4-(2-(1,3-Dibutyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[2,1-f]purin-9(6H)-yl)ethyl)phenoxy)-N-(3-(diethylamino)-propyl)acetamide (27) and the corresponding N-(2-(pyrrolidin-1-yl)ethylacetamide (36) were found to be the most potent antagonist of the present series. While 27 showed CYP inhibition and moderate metabolic stability, 36 was found to possess suitable properties for in vivo application. In attempt to explain the affinity data for the synthesized compounds, the molecular modeling and docking study was performed using homology models of A1 and A2A adenosine receptors. The potent compound 36 was used as an example for discussion of the possible ligand-protein interactions. Moreover, the compounds showed high water-solubility indicating that the approach of introducing a basic side chain was successful for the class of generally poorly soluble AR antagonists.

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Publication details

The article was received on 06 Feb 2018, accepted on 25 Apr 2018 and first published on 14 May 2018


Article type: Research Article
DOI: 10.1039/C8MD00070K
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Tricyclic xanthine derivatives containing a basic substituent: adenosine receptor affinity and drug-related properties

    M. Zaluski, K. Stanuch, T. Karcz, S. Hinz, G. Latacz, E. Szymańska, J. Schabikowski, A. Doroz-Plonka, J. Handzlik, A. Drabczynska, C. E. Muller and K. Kononowicz, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00070K

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