title: Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.
abstract: Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (approximately 100%) in rats, high potency (ET(A) IC(50) = 0.08 nM), and optimal ET(A)/ET(B) selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).
authors.affiliation: Encysive Pharmaceuticals Inc., 7000 Fannin, Houston, TX 77030, USA. cwu@encysive.com
authors.forename: Chengde
authors.initials: C
authors.lastname: Wu
authors.forename: E Radford
authors.initials: ER
authors.lastname: Decker
authors.forename: Natalie
authors.initials: N
authors.lastname: Blok
authors.forename: Huong
authors.initials: H
authors.lastname: Bui
authors.forename: Tony J
authors.initials: TJ
authors.lastname: You
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Andree R
authors.initials: AR
authors.lastname: Bourgoyne
authors.forename: Vippra
authors.initials: V
authors.lastname: Knowles
authors.forename: Kurt L
authors.initials: KL
authors.lastname: Berens
authors.forename: George W
authors.initials: GW
authors.lastname: Holland
authors.forename: Tommy A
authors.initials: TA
authors.lastname: Brock
authors.forename: Richard A F
authors.initials: RA
authors.lastname: Dixon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; D008024:Ligands; C485107:N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide; D044022:Receptor, Endothelin A; D013450:Sulfones