Design, synthesis and evaluation of 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives as ETA receptor selective antagonists using FRET assay

The endothelin axis and in particular the two receptor subtypes, ET_A and ET_B, are under investigation for the treatment of various diseases such as pulmonary arterial hypertension, fibrosis, renal failure and Cancer. Previous work in our lab has shown that 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives exhibit noteworthy Endothelin Receptor Antagonist activity. A series of analogues with modifications centered around position 6 of the heterocyclic Quinolone core and replacement of the aryl carboxylic acid group with an isosteric tetrazole ring was designed and synthesized to further optimize the structure activity relationship. The Endothelin Receptor Antagonist activity was determined by in vitro Förster resonance energy transfer (FRET) using GeneBLAzer® assay technology. The most potent member of this series exhibited ET_A receptor antagonist activity in the subnanomolar range with an IC₅₀ value of 0.8nM, and was 1000-fold selective for the ET_A receptor compared to the ET_B receptor. Its activity and selectivity profile resembles that of the most recently approved drug, macitentan.

4-Oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives; ET(A) receptor selectivity; Endothelin receptor antagonists; FRET assay.