Please use this identifier to cite or link to this item: https://doi.org/10.1021/jm101349u
Title: Synthesis and biological evaluation of a new series of 1, 2, 4-triazolo[1, 5-α]-1, 3, 5-triazines as human a 2a adenosine receptor antagonists with improved water solubility
Authors: Federico, S.
Paoletta, S.
Cheong, S.L. 
Pastorin, G. 
Cacciari, B.
Stragliotto, S.
Norbert Klotz, K.
Siegel, J.
Gao, Z.-G.
Jacobson, K.A.
Moro, S.
Spalluto, G.
Issue Date: 10-Feb-2011
Citation: Federico, S., Paoletta, S., Cheong, S.L., Pastorin, G., Cacciari, B., Stragliotto, S., Norbert Klotz, K., Siegel, J., Gao, Z.-G., Jacobson, K.A., Moro, S., Spalluto, G. (2011-02-10). Synthesis and biological evaluation of a new series of 1, 2, 4-triazolo[1, 5-α]-1, 3, 5-triazines as human a 2a adenosine receptor antagonists with improved water solubility. Journal of Medicinal Chemistry 54 (3) : 877-889. ScholarBank@NUS Repository. https://doi.org/10.1021/jm101349u
Abstract: The structure-activity relationship (SARof 1, 2, 4-triazolo[1, 5-a]-1, 3, 5-triazine derivatives related to ZM241385 as antagonists of the A 2A adenosine receptor (ARwas explored through the synthesis of analogues substituted at the 5 position. The A 2A AR X-ray structure was used to propose a structural basis for the activity and selectivity of the analogues and to direct the synthetic design strategy to provide access to solvent-exposed regions. Thus, we have identified a point of substitution for the attachment of solubilizing groups to enhance both aqueous solubility and physicochemical properties, maintaining potent interactions with the A 2A AR and, in some cases, receptor subtype selectivity. Among the most potent and selective novel compounds were a long-chain ether-containing amine congener 20 (K i 11.5 nMand its urethane-protected derivative 14 (K i 17.8 nM). Compounds 20 and 31 (K i 11.5 and 16.9 nM, respectivelywere readily water-soluble up to 10 mM. The analogues were docked in the crystallographic structure of the hA 2A AR andina homology model of the hA 3 AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed. © 2011 American Chemical Society.
Source Title: Journal of Medicinal Chemistry
URI: http://scholarbank.nus.edu.sg/handle/10635/106391
ISSN: 00222623
DOI: 10.1021/jm101349u
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