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

Abstract

We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2Ј-methyl[1,1Ј-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1).We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Premature birth is a major problem in obstetrics affecting about 10% of all births and being the largest cause of perinatal morbidity and mortality. The impact on society is significant in terms of costs of neonatal intensive care and for the emotional and social stress to the family. The physiopathology of human preterm labor is complex and multifactorial. Preterm increase of uterine activity is a common complication of pregnancy and accounts for many cases of preterm labor. Pharmacological interventions aimed at maintaining uterine quiescence (tocolysis) have been, and are likely to remain, the cornerstone of pharmaceutical management of preterm labor. However, current tocolytic agents (␤-mimetics, magnesium sulfate, calcium channel blockers, or prostaglandin synthesis inhibitors) suffer from a minimal effectiveness and show important fetal and maternal side effects. Therefore, it is obvious that a safe and effective oral treatment delaying spontaneous preterm birth would have tremendous clinical benefits.The peptide hormone oxytocin (OT) is a potent contractor of the human uterus. OT mediates its effect through activation of the G protein-coupled oxytocin receptor (OT-R) that is expressed in myometrial cells. OT-R is coupled to phospholipase C activation, leading to intracellular synthesis of inositol phosphates and mobilization of calcium. In turn, the rise in intracellular calcium concentration promotes a cascade of events, including phosphorylation of myosin, that then acts on actin and induces uterine muscle cell contraction. Before onset of labor and in the term myometrium, the OT-R density Article, publication date, and citation information can be found at

Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

“…It was equipotent at rat OT and V2 receptors and 10-fold selective for rat OT vs. rat V1 receptors ( Table 1). The selectivity of atosiban was very similar to that reported in the literature by various groups (6,20,36). For example, Cirillo et al (6) found that atosiban was 23-fold more potent at hV1a than hOT and only 8 and 12-fold more potent at hOT than V1b and V2, respectively.…”

“…Recently discovered nonpeptide antagonists are reported to have much better selectivity for OTR vs. V1aR; however, none approach the selectivity of GSK221149A. For example, the compounds described by Cirillo et al (6), Serradeil-Le Gal et al (31) (SSR126768A), and Bell et al (2) (L-372,662) are 6-, 95-, and 609-fold selective for hOTR vs. hV1aR, while GSK221149A is Ͼ18,000-fold selective. In addition, GSK221149A (1,500-fold) is much more selective than SSR126768A (62-fold) at rat OTR vs. rat V1a (data for the other two previously mentioned nonpeptide antagonists are lacking).…”

“…It has been shown to reduce uterine contractions in vitro and in vivo and arrest preterm labor in pregnant women, resulting in a delay of delivery (13). While atosiban is efficacious at delaying delivery for 48 h, its use to prolong pregnancy beyond 48 h has been limited because it is only available for parenteral administration.Significant progress has been made in identifying both peptide and nonpeptide oxytocin receptor antagonists (1,6,20,25, 27,31,32,37). However, even though the newly developed peptide antagonists [such as barusiban and those described by Manning et al (20) and Stymiest et al (32)] are more potent and selective and serve as good research tools, their use in the clinic is still limited by having to be administered parenterally.…”

OBE022, an Oral and Selective Prostaglandin F2α Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor

“…This captures the overall effect on contraction work rate including intensity, frequency and length of single contractions (Cirillo et al, 2003(Cirillo et al, , 2007. Both OBE022, given orally, and OBE002, administered i.v., reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days (GD) 19-21 ( Figure 6).…”

“…Experimental conditions described by Cirillo et al, 2003Cirillo et al, , 2007 For the oral administration the same computation procedure was applied at different time points after treatment.…”