title: The effects of diminishing albumin binding to some Endothelin receptor antagonists.
abstract: As a pharmacological class, Endothelin-A receptor (ET(A)) antagonists are highly bound (>98%) to serum albumin. In the presence of physiological concentrations of albumin, their affinities for ET(A) decrease 10 to 100 fold. We have prepared ET(A) antagonists which exhibit lower degrees of binding to albumin, while maintaining potency and selectivity for the ET(A) receptor. The protein induced IC50 shift is reduced or eliminated in this new series of compounds. The compounds also display altered in vivo and pharmacokinetic profiles which may be consistent with their lower degree of protein binding.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA. bruce.g.szczepankiewicz@abbott.com
authors.forename: B G
authors.initials: BG
authors.lastname: Szczepankiewicz
authors.forename: R B
authors.initials: RB
authors.lastname: Bal
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: J R
authors.initials: JR
authors.lastname: Wu-Wong
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: D B
authors.initials: DB
authors.lastname: Dixon
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
authors.forename: D J
authors.initials: DJ
authors.lastname: Hoffman
authors.forename: A J
authors.initials: AJ
authors.lastname: Borre
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: B N
authors.initials: BN
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D000077868:Atrasentan; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D019334:Endothelin-3 / Q000378:metabolism; D006801:Humans; D008297:Male; D011485:Protein Binding; D011759:Pyrrolidines / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D012709:Serum Albumin; D000077868:Atrasentan