Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists.
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.
Quattropani
Anna
A
Serono Pharmaceutical Research Institute, Departments of Chemistry and Biochemical Pharmacology, 14 Chemin des Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland.
Dorbais
Jérôme
J
Covini
David
D
Pittet
Pierre-André
PA
Colovray
Véronique
V
Thomas
Russell J
RJ
Coxhead
Richard
R
Halazy
Serge
S
Scheer
Alexander
A
Missotten
Marc
M
Ayala
Guidon
G
Bradshaw
Charles
C
De Raemy-Schenk
Anne-Marie
AM
Nichols
Anthony
A
Cirillo
Rocco
R
Tos
Enrico Gillio
EG
Giachetti
Claudio
C
Golzio
Lucia
L
Marinelli
Paolo
P
Church
Dennis J
DJ
Barberis
Claude
C
Chollet
André
A
Schwarz
Matthias K
MK
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
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