title: Acyl substitution at the ortho position of anilides enhances oral bioavailability of thiophene sulfonamides: TBC3214, an ETA selective endothelin antagonist.
abstract: Sitaxsentan (3, TBC11251) (Wu et al. J. Med. Chem. 1997, 40, 1690) is an orally active ET(A) selective endothelin antagonist that attenuates pulmonary vascular hypertension and cardiac hypertrophy in rats (Tilton et al. Pulm. Pharmacol. Ther. 2000, 13, 87). It has demonstrated efficacy in a phase II clinical trial for congestive heart failure (Givertz et al. Circulation 2000, 101, 2922). During the discovery of 3, we observed several structure-oral bioavailability relationships. To investigate whether there is any generality in these trends, we synthesized some similar pairs of compounds in the latest series (Wu et al. J. Med. Chem. 1999, 42, 4485) and evaluated their oral properties. In both series, an acyl group at the 2-position of the anilide of these thiophene sulfonamides improved oral bioavailability. As a result of this exercise, TBC3214 (17) was identified as a sitaxsentan follow-on candidate. It is very potent (IC(50) for ET(A) = 40 pM) and highly selective for ET(A) vs ET(B) receptors (400 000-fold), with a half-life of >4 h and oral bioavailability of 25% in rats, 42% in cats, and 70% in dogs.
authors: Department of Chemistry, Texas Biotechnology Corporation, 7000 Fannin, Suite 1920, Houston, Texas 77030, USA. cwu@tbc.com
authors: C
authors: C
authors: Wu
authors: E R
authors: ER
authors: Decker
authors: N
authors: N
authors: Blok
authors: J
authors: J
authors: Li
authors: A R
authors: AR
authors: Bourgoyne
authors: H
authors: H
authors: Bui
authors: K M
authors: KM
authors: Keller
authors: V
authors: V
authors: Knowles
authors: W
authors: W
authors: Li
authors: F D
authors: FD
authors: Stavros
authors: G W
authors: GW
authors: Holland
authors: T A
authors: TA
authors: Brock
authors: R A
authors: RA
authors: Dixon
mesh_terms: D000284:Administration, Oral; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002415:Cats; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008958:Models, Molecular; D051381:Rats; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000813:Anilides; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C424912:TBC 3214