Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor

• Published in: The Journal of pharmacology and experimental therapeutics 2003-07, Vol.306 (1), p.253-261
• Main Authors: Cirillo, Rocco, Gillio Tos, Enrico, Schwarz, Matthias K, Quattropani, Anna, Scheer, Alexander, Missotten, Marc, Dorbais, Jerome, Nichols, Anthony, Borrelli, Francesco, Giachetti, Claudio, Golzio, Lucia, Marinelli, Paolo, Thomas, Russell J, Chevillard, Claude, Laurent, Florence, Portet, Karine, Barberis, Claude, Chollet, Andre
• Format: Article
• Language: English
• Subjects: Anesthesia; Animals; Cells, Cultured; CHO Cells; Cricetinae; Dinoprost - pharmacology; Dose-Response Relationship, Drug; Female; Humans; Imines - pharmacology; Oxytocin - pharmacology; Pregnancy; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Oxytocin - antagonists & inhibitors; Receptors, Vasopressin - metabolism; Uterine Contraction - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.049395

We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2 S ,4 Z )- N -[(2 S )-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1 ). We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Compound 1 competitively inhibits binding of [ 3 H]oxytocin and the peptide antagonist 125 I-ornithine vasotocin analog to human and rat oxytocin receptor expressed in human embryonic kidney 293-EBNA or Chinese hamster ovary cells with nanomolar potency. Selectivity against vasopressin receptor subtypes is >6-fold for V1a and >350-fold for V2 and V1b. Compound 1 inhibits oxytocin-evoked intracellular Ca 2 + mobilization (IC 50 = 8 nM). Compound 1 has no intrinsic agonist activity at the oxytocin receptor. Oxytocininduced contraction of isolated rat uterine strips is blocked by compound 1 (p A 2 = 7.82). In anesthetized nonpregnant rats, single administration of compound 1 by i.v. or oral routes causes dose-dependent inhibition of contractions elicited by repeated injections of oxytocin with ED 50 = 3.5 mg/kg i.v. and 89 mg/kg p.o., respectively. Compound 1 significantly inhibits spontaneous uterine contractions in pregnant rats near term when administered intravenously or orally. We conclude that compound 1 is a potent, selective, and orally active nonpeptide oxytocin receptor antagonist, which is a suitable candidate for evaluation as a potential tocolytic agent for the management of preterm labor.