Synthesis and pharmacological activity of 1,3,6-trisubstituted-4-oxo-1,4- dihydroquinoline-2-carboxylic acids as selective ET_A antagonists

A series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (2a-m) were designed and synthesized and their pharmacological activity determined, with the objective to better understand their SAR as potential ET_A selective inhibitors. Most of the compounds displayed significant ET_A antagonist activity having IC₅₀ for inhibition of binding of the [¹²⁵I]ET-1 to ET_A receptor <10 nM, with good selectivity for ET_A antagonism over ET_B receptor. Based on the in vitro results, SAR of this series of compounds requires an alkoxy substituent at the 6-position to be a straight and saturated chain up to three carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease in ET_A antagonist activity. In this series, compound 2c (6-O-n-propyl analog) was found to be most potent (IC ₅₀ = 0.11 nM) with ET_B/ET_A selectivity of 8303.