Key result
The ethenesulfonamide derivative 6u demonstrated potent ETA-selective receptor antagonism and effectively inhibited the pressor response to big ET-1 in rats with an oral ID50 of /kg.
Structural modifications of 2-phenylethenesulfonamide derivatives yielded novel ETA/ETB mixed and ETA-selective antagonists with potent in vitro and in vivo activities.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for oral ETA-selective antagonists; leaves open translation to human ET-1-mediated disease.
In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.
No takes yet. Share an insight, caveat, or question.
Harada et al. (2001) studied Hypertension (preclinical models). Ethenesulfonamide derivatives (e.g., 6s, 6t, 6u) vs. Vehicle/Baseline was evaluated on ETA and ETB receptor binding affinity (IC50) and inhibition of pressor response to big ET-1. The ethenesulfonamide derivative 6u demonstrated potent ETA-selective receptor antagonism and effectively inhibited the pressor response to big ET-1 in rats with an oral ID50 of /kg.
Synapse has enriched 10 related papers. Consider them for comparative context: