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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 26, 2003; DOI: 10.1124/jpet.103.049395

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Rocco Cirillo
Enrico Gillio Tos
Matthias K. Schwarz
Anna Quattropani
Alexander Scheer
Marc Missotten
Jerome Dorbais
Anthony Nichols
Francesco Borrelli
Claudio Giachetti
Lucia Golzio
Paolo Marinelli
André Chollet
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*Compound via MeSH
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Hazardous Substances DB
*OXYTOCIN
*PROSTAGLANDIN F2ALPHA


Received for publication January 24, 2003.
Revised February 24, 2003.
Accepted for publication March 13, 2003.

PHARMACOLOGY OF (2S,4Z)-N-[(2S)-2-HYDROXY-2-PHENYLETHYL]-4-(METHOXYIMINO)- 1-[(2'-METHYL[1,1'-BIPHENYL]-4-YL)CARBONYL]-2-PYRROLIDINEC ARBOXAMIDE, A NEW POTENT AND SELECTIVE NON-PEPTIDE ANTAGONIST OF THE OXYTOCIN RECEPTOR

Rocco Cirillo 1, Enrico Gillio Tos 2, Matthias K. Schwarz 3, Anna Quattropani 3, Alexander Scheer 3, Marc Missotten 3, Jerome Dorbais 3, Anthony Nichols 3, Francesco Borrelli 1, Claudio Giachetti 1, Lucia Golzio 1, Paolo Marinelli 1, Russell J. Thomas 4, Claude Chevillard 5, Florence Laurent 5, Karine Portet 5, Claude Barberis 5, André Chollet 3*

1 Istituto di Ricerche Biomediche 'A. Marxer' LCG-RBM 2 stituto di Ricerche Biomediche 'A. Marxer' LCG-RBM 3 Serono Pharmaceutical Research Institute 4 Evotec OAI 5 INSERM

* Address correspondence to: E-mail: andre.chollet{at}serono.com

Abstract

We have discovered a new, potent, selective and orally active oxytocin receptor antagonist, (1). We report the biochemical, pharmacological and pharmacokinetic characterization in vitro and in vivo of this compound. (1) competitively inhibits binding of 3H-oxytocin and the peptide antagonist 125I-OVTA to human and rat oxytocin receptor expressed in HEK293-EBNA or CHO cells with nanomolar potency. Selectivity against vasopressin receptor subtypes is >6-fold for V1a and >350-fold for V2 and V1b. (1) inhibits oxytocin-evoked intracellular Ca2+ mobilization (IC50=8nM). (1) has no intrinsic agonist activity at the oxytocin receptor. Oxytocin-induced contraction of isolated rat uterine strips is blocked by (1) (pA2=7.82). In anesthetized non-pregnant rats, single administration of (1) by i.v. or oral routes causes dose-dependent inhibition of contractions elicited by repeated injections of oxytocin with ED50=3.5 mg/kg i.v. and 89 mg/kg p.o., respectively. (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 non-peptide oxytocin receptor antagonist, which is a suitable candidate for evaluation as a potential tocolytic agent for the management of preterm labor.


Key words: atosiban, oxytocin antagonist, preterm labor, ritodrine, tocolysis, uterine contraction


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