title: Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists.
abstract: We report a novel chemical class of potent oxytocin receptor antagonists showing a high degree of selectivity against the closely related vasopressin receptors (V1a, V1b, V2). An initial compound, 7, was shown to be active in an animal model of preterm labor when administered by the intravenous but not by the oral route. Stepwise SAR investigations around the different structural elements revealed one position, the arenesulfonyl moiety, to be amenable to structural changes. Consequently, this position was used to introduce a variety of substituents to improve the physicochemical properties. Some of the resulting analogues were found to be superior to 7 both in terms of potency in vitro and aqueous solubility, which translated into significantly improved efficacy in the animal model after intravenous and oral administration. The best compound, 73, potently inhibited oxytocin-induced uterine contractions in nonpregnant rats and reduced spontaneous uterine contractions in late-term pregnant rats.
authors.affiliation: Serono Pharmaceutical Research Institute, Departments of Chemistry and Biochemical Pharmacology, 14 Chemin des Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Quattropani
authors.forename: Jérôme
authors.initials: J
authors.lastname: Dorbais
authors.forename: David
authors.initials: D
authors.lastname: Covini
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Pittet
authors.forename: Véronique
authors.initials: V
authors.lastname: Colovray
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Thomas
authors.forename: Richard
authors.initials: R
authors.lastname: Coxhead
authors.forename: Serge
authors.initials: S
authors.lastname: Halazy
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheer
authors.forename: Marc
authors.initials: M
authors.lastname: Missotten
authors.forename: Guidon
authors.initials: G
authors.lastname: Ayala
authors.forename: Charles
authors.initials: C
authors.lastname: Bradshaw
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: De Raemy-Schenk
authors.forename: Anthony
authors.initials: A
authors.lastname: Nichols
authors.forename: Rocco
authors.initials: R
authors.lastname: Cirillo
authors.forename: Enrico Gillio
authors.initials: EG
authors.lastname: Tos
authors.forename: Claudio
authors.initials: C
authors.lastname: Giachetti
authors.forename: Lucia
authors.initials: L
authors.lastname: Golzio
authors.forename: Paolo
authors.initials: P
authors.lastname: Marinelli
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Church
authors.forename: Claude
authors.initials: C
authors.lastname: Barberis
authors.forename: André
authors.initials: A
authors.lastname: Chollet
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007752:Obstetric Labor, Premature / Q000503:physiopathology / Q000517:prevention & control; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: C507728:3-(4-((4-chloro(2-oxo-2-(2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino)ethyl)anilino)sulfonyl)phenyl)-N-(3-(dimethylamino)propyl)propanamide; D065092:Antidiuretic Hormone Receptor Antagonists; D006834:Hydrazines; D018045:Receptors, Oxytocin; D013449:Sulfonamides