Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist

Journal of Medicinal Chemistry
C WuR A Dixon

Abstract

Previously we reported the discovery of amidothiophenesulfonamides as endothelin receptor-A antagonists with high potency and selectivity. Replacement of an amide group in this class of compounds with an acetyl group maintained the in vitro binding affinity and in vivo activity while providing a compound with oral bioavailability and longer duration of action. The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. The compound has a serum half-life in the rat and the dog of 6-7 h and 60-100% oral bioavailability. This compound is one of the most selective ETA antagonists reported and therefore is suitable for additional pharmacological and clinical investigation of the role of ETA receptors in diseases.

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Citations

Aug 6, 2013·Current Hypertension Reports·Rebecca C MoorhouseNeeraj Dhaun
Feb 26, 2004·Bioorganic & Medicinal Chemistry Letters·Govindarajulu BabuJim-Min Fang
Mar 19, 1999·European Journal of Pharmacology·J R Wu-WongT J Opgenorth
May 6, 2003·Bioorganic & Medicinal Chemistry Letters·Udo E W LangeGeorg Kettschau
Oct 6, 2000·Drug Discovery Today·A RayJ B Gupta
May 25, 2013·Science·Hirohito HarukiKai Johnsson
Nov 14, 2006·Postgraduate Medical Journal·D J Fox, R S Khattar
May 12, 2009·American Journal of Physiology. Heart and Circulatory Physiology·David B MurrayJoseph S Janicki
Nov 25, 2003·American Journal of Respiratory and Critical Care Medicine·Robyn J BarstUNKNOWN STRIDE-1 Study Group
Jun 1, 2001·Chemical & Pharmaceutical Bulletin·H HaradaI Yanagisawa
Dec 31, 2010·Vascular Health and Risk Management·Samuel T Nadler, Jeffrey D Edelman
Apr 7, 2011·Vascular Health and Risk Management·Zeenat Safdar
Jul 1, 2007·Future Cardiology·Reda E Girgis, Richard Af Dixon
Nov 22, 2011·Revue des maladies respiratoires·S Boniface, M Reynaud-Gaubert
Aug 21, 2010·Canadian Journal of Physiology and Pharmacology·Faquan LiangKelly R Pitts
Oct 27, 2004·Expert Opinion on Investigational Drugs·Evelyn M HornRobyn J Barst
Jul 12, 2008·Expert Opinion on Investigational Drugs·Frank EnseleitFrank Ruschitzka
Dec 15, 2006·Current Medical Research and Opinion·Avrum JacobsMardi Gomberg-Maitland
Jul 14, 2004·Chest·David B BadeschUNKNOWN American College of Chest Physicians
Nov 15, 2011·Pulmonary Pharmacology & Therapeutics·Julio SandovalUNKNOWN STRIDE-4 investigators
Mar 10, 2016·Pharmacological Reviews·Anthony P DavenportJanet J Maguire
Apr 20, 2006·International Journal of Clinical Practice·D S O'Callaghan, S P Gaine
Apr 22, 2010·Cardiovascular Therapeutics·Shahzad G Raja
Aug 15, 2012·Birth Defects Research. Part B, Developmental and Reproductive Toxicology·David M CrossFiona L Stavros
Oct 13, 2005·Pharmacology & Therapeutics·Sophie MotteRobert Naeije
Aug 9, 2005·Bioorganic & Medicinal Chemistry·Anelia Ts MavrovaMitka K Micheva
Jul 20, 2011·Nature Reviews. Cardiology·Dermot S O'CallaghanMarc Humbert
Feb 15, 2007·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·Neal J Benedict
Nov 19, 2005·Expert Review of Cardiovascular Therapy·Allison C WidlitzEvelyn M Horn

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