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Discovery and Development of a New Class of Potent, Selective, Orally Active Oxytocin Receptor Antagonists
journal contribution
posted on 2005-12-01, 00:00 authored by Anna Quattropani, Jérôme Dorbais, David Covini, Pierre-André Pittet, Véronique Colovray, Russell J. Thomas, Richard Coxhead, Serge Halazy, Alexander Scheer, Marc Missotten, Guidon Ayala, Charles Bradshaw, Anne-Marie De Raemy-Schenk, Anthony Nichols, Rocco Cirillo, Enrico Gillio Tos, Claudio Giachetti, Lucia Golzio, Paolo Marinelli, Dennis J. Church, Claude Barberis, André Chollet, Matthias K. SchwarzWe 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.
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compoundvasopressinpotentlyselectivityNewanaloguelaborStepwise SAR investigationsphysicochemicalefficacypretermvarietyuterineadministrationnovel chemical classSelectiveanimal modelmoietyOxytocin Receptor Antagoniststermsolubility1bOrallypotencysubstituentcontractionnonpregnantarenesulfonyloxytocin receptor antagonistsPotent1a
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