Synthesis and pharmacological activity of 1,3,6-trisubstituted-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid derivatives as selective ET(A) antagonists

Endothelin-1 (ET-1) is a member of a novel family of vasoconstrictors, which consists of 21 amino acid residues, with two intra-chain disulfide linkages. ET-1 is recognized as the major isoform of relevance in human physiology and pathophysiology. It is involved in a variety of diseases, including systemic and pulmonary hypertension, congestive heart failure, renal failure, cancer, preterm labor and cerebrovascular disease. ET-1 exerts its biological effects through the stimulation of 2 subtypes of receptors, endothelin receptor subtype A (ETA) and endothelin receptor subtype B (ETB). ET A receptors mediate most of the actions of ET-1 associated with these pathological conditions, suggesting that a selective ETA receptor antagonist would be useful as a therapeutic agent for treatment of these chronic pathological conditions.*;A series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (12a-m) were designed and synthesized as potential ETA selective inhibitors. Among the compounds tested, 6-O-ethyl (12b), 6-O-n-propyl (12c), 6-O- n-butyl (12g), 6-O-i-butyl ( 12h)), 6-O-sec-butyl (12i), and 6-O-propan-3-ol (12l) 4-oxo-1,4-dihydroquinoline diacids displayed significant ETA antagonist activity having IC50 for inhibition of binding of the [125I]ET-1 to ETA receptor less than 10 nM. These compounds also showed good selectivity for ET A antagonism over ETB receptor. The SAR requires an alkyloxy substituent at the 6-position to be a straight and saturated chain up to 3 carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease in ETA antagonist activity. Polar hydrophilic groups at 6-position are detrimental for ETA antagonist activity as seen by a decrease in activity when replaced by 6-O-propan-3-ol ( 12l) and 6-O-carboxymethyl (12m) at the 6-position of the quinoline ring. Compound 12c was found to be most potent (IC50 = 0.11 nM) with ETB/ETA selectivity of 8303. In vivo, compound 12a (6-OH), a prototype compound of this 4-oxo-1,4-dihydroquinolone diacids series, was shown to reduce lung inflammation and preterm labor in two different animal models. Compounds 12a and 12c showed no acute toxicity up to a dose of 200 mg/kg and also no adverse neurological effects at this dose. Though 4-oxo-1,4-dihydroquinoline diacids derivatives showed activity in both animal models, chronic toxicity studies have to be done for their complete evaluation as ETA receptor antagonists.;*Please refer to dissertation for diagrams.