Structure–Activity Relationships and Molecular Modeling of 1,2,4-Triazoles as Adenosine Receptor Antagonists

Carlsson J, Tosh DK, Phan K, Gao ZG, Jacobson KA

ACS Med. Chem. Lett. 3 (9) 715-720 [2012-09-13; online 2012-08-07]

The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A(2A) adenosine receptor (hA(2A)AR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA(2A)AR were tested in hA(1), A(2A), and A(3) radioligand binding assays and in functional assays for the A(2B)AR subtype. As a series of closely related analogs of the initial lead, 1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of 32, a hA(2A)AR antagonist (K(i) 200 nM) with high ligand efficiency. In the light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A(2A)AR crystal structures.

Jens Carlsson

PubMed 23342198

DOI 10.1021/ml300097g

Crossref 10.1021/ml300097g


Publications 7.1.2