Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 20, Pages 6120-6134Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.08.026
Keywords
2-Phenyl-pyrazolo-triazolo-pyrimidines; Human A(3) adenosine receptor antagonists; Structure-affinity relationship; Affinity; Selectivity
Funding
- National University of Singapore [R-148-000-129-112]
- Ministry of Education [MOE2009-T2-2-011, R-398-000-068-112]
- A-STAR [R-148-001-435-305]
- University of Padova, Italy
- Italian Ministry for University and Research, Rome, Italy (MIUR) [200834TC4L_002]
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In an attempt to study the optimal combination of a phenyl ring at the C-2-position and different substituents at the N-5- and N-8-positions towards the selective modulation of human A(3) adenosine receptors (hA(3)AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N-8 and chains of variable length at N-5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA(3)AR in the low nanomolar range. Compound 16 possessed the best hA(3)AR affinity and selectivity profile (K(i)hA(3) = 1.33 nM; hA(1)/hA(3) = 4880; hA(2A)/hA(3) = 1100) in the present series of2-(substituted)phenylpyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA3AR. (C) 2011 Elsevier Ltd. All rights reserved.
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