Endothelin Antagonists:  Substituted Mesitylcarboxamides with High Potency and Selectivity for ET_A Receptors

Abstract

We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. #3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation 1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ET(A) selectivity by approximately 10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has approximately 10-fold higher ET(A) binding affinity than 1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.

An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs

“…Using comparative molecular field analysis (CoMFA) for the correlation of the steric and electronic field environment a number of GPCR lead compounds were optimized (29,30). For instance, successful ligand optimization for dopamine (31,32), serotonin (33,34), endothelin (35), and adenosine (36, 37) receptors has been reported for CoMFA. Moreover, ligand selectivity has also been addressed by demonstrating side affinities for a series of aryl piperazines active against the serotonin 5-HT1A receptor for the 1-adrenergic receptor (38).…”

An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension

“…This has led to the successful development of therapeutic strategies through the application of endothelin receptor antagonists (ETRAs) (Abman, 2009). Sitaxentan, the sodium salt of 4-chloro-3-methyl-5-{2- [2-(6-methylbenzo[d] [1,3]dioxol-5-yl) acetyl]-3-thienylsulfonamido}isoxazole, is an ETRA with high oral bioavailability, a long duration of action, and high specificity for the ET A receptor (Tilton et al, 2000;Wu et al, 1997Wu et al, , 1999. Sitaxentan sodium (TBC11251Na) was marketed under the trade name Thelin Ò ; however, in December 2010 it was withdrawn worldwide because of emerging safety information from clinical trials and post-marketing clinical case reports.…”

Effect of transition from sitaxsentan to ambrisentan in pulmonary arterial hypertension

“…Based on in vitro competitive receptor binding assay, ambrisentan has a 77-fold affinity for ET A compared with ET B receptors 3. On the other hand, sitaxsentan has a ∼6500-fold affinity for ET A compared with ET B receptors 4,5. Activation of the ET A receptor on smooth muscle cells causes sustained vasoconstriction and proliferation of these cells.…”