title: 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.
authors.affiliation: Texas Biotechnology Corporation, 7000 Fannin, Suite 1920, Houston, Texas 77030, USA. cwu@tbc.com
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: E R
authors.initials: ER
authors.lastname: Decker
authors.forename: N
authors.initials: N
authors.lastname: Blok
authors.forename: H
authors.initials: H
authors.lastname: Bui
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Raju
authors.forename: A R
authors.initials: AR
authors.lastname: Bourgoyne
authors.forename: V
authors.initials: V
authors.lastname: Knowles
authors.forename: R J
authors.initials: RJ
authors.lastname: Biediger
authors.forename: R V
authors.initials: RV
authors.lastname: Market
authors.forename: S
authors.initials: S
authors.lastname: Lin
authors.forename: B
authors.initials: B
authors.lastname: Dupré
authors.forename: T P
authors.initials: TP
authors.lastname: Kogan
authors.forename: G W
authors.initials: GW
authors.lastname: Holland
authors.forename: T A
authors.initials: TA
authors.lastname: Brock
authors.forename: R A
authors.initials: RA
authors.lastname: Dixon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D006207:Half-Life; D006976:Hypertension, Pulmonary / Q000097:blood / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; C401381:TBC 2576; D013876:Thiophenes