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Eur J Med Chem. 2016 Jan 27;108:117-33. doi: 10.1016/j.ejmech.2015.11.015. Epub 2015 Nov 17.

Structural refinement of pyrazolo[4,3-d]pyrimidine derivatives to obtain highly potent and selective antagonists for the human A3 adenosine receptor.

Author information

  • 1Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
  • 2Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
  • 3Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, via Marzolo 5, 35131, Padova, Italy.
  • 4Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, via Marzolo 5, 35131, Padova, Italy. Electronic address: stefano.moro@unipd.it.
  • 5Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy. Electronic address: vittoria.colotta@unifi.it.

Abstract

In previous research, we identified some 7-oxo- and 7-acylamino-substituted pyrazolo[4,3-d]pyrimidine derivatives as potent and selective human (h) A3 adenosine receptor (AR) antagonists. Herein we report on the structural refinement of this class of antagonists aimed at achieving improved receptor-ligand recognition. Hence, substituents with different steric bulk, flexibility and lipophilicity (Me, Ar, heteroaryl, CH2Ph) were introduced at the 5- and 2-positions of the bicyclic scaffold of both the 7-oxo and 7-amino derivatives, and acyl residues were appended on the 7-amino group of the latter. All the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amines and 7-acylamines bearing a 4-methoxyphenyl- or a 2-thienyl group at the 5-position showed high hA3 affinity and selectivity. In particular, the 2-phenyl-5-(2-thienyl)-pyrazolo[4,3-d]pyrimidin-7-(4-methoxybenzoyl)amine 25 (Ki = 0.027 nM) is one of the most potent and selective hA3 antagonists reported so far. By using an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinities were critically described.

KEYWORDS:

Adenosine receptor antagonists; G-protein-coupled receptors; Ligand-receptor modeling studies; Pyrazolopyrimidines

PMID:
26638043
DOI:
10.1016/j.ejmech.2015.11.015
[PubMed - indexed for MEDLINE]
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