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ENDOCRINE AND REPRODUCTIVE

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

Istituto di Ricerche Biomediche "A. Marxer", LCG Bioscience, Colleretto Giacosa, Italy (R.C., E.G.T., F.B., C.G., L.G., P.M.); Institut National de la Santé et de la Recherche Médicale U469, Montpellier, France (C.C., F.L., K.P., C.B.); Evotec OAI, Milton Park, Abingdon, United Kingdom (R.J.T.); and Serono Pharmaceutical Research Institute, Geneva, Switzerland (M.K.S., A.Q., A.S., M.M., J.D., A.N., A.C.)

We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-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 [³H]oxytocin and the peptide antagonist ¹²⁵I-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 Ca²⁺ mobilization (IC₅₀ = 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 (pA₂ = 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 ED₅₀ = 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.

Address correspondence to: Dr. André Chollet, Serono Pharmaceutical Research Institute, 14, Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland. E-mail: andre.chollet{at}serono.com

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