当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists.

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists.

Abstract：

:A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (Ki < 30 nM) and exquisite selectivity. The structure-activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA2BAR and the eutomer of the most attractive novel antagonist ( S )-18g (Ki = 3.66 nM) was validated.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Mallo-Abreu A,Prieto-Díaz R,Jespers W,Azuaje J,Majellaro M,Velando C,García-Mera X,Caamaño O,Brea J,Loza MI,Gutiérrez-de-Terán H,Sotelo E

doi

10.1021/acs.jmedchem.0c00564

subject

Has Abstract

pub_date

2020-07-23 00:00:00

pages

7721-7739

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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