SSR126768A (4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2- oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, Hydrochloride): A New Selective and Orally Active Oxytocin Receptor Antagonist for the Prevention of Preterm Labor

Abstract

4-Chloro-3-[(3R)-(ϩ)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (K i ϭ 0.44 nM) and exhibited much lower affinity for V 1a , V 1b , and V 2 receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 M). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I 125 ]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca 2ϩ increase (K i ϭ 0.50 nM) and prostaglandin release (K i ϭ 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA 2 ϭ 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor.Preterm labor (at less than 37 completed weeks of gestation) occurs in approximatively 10% of births, accounts for 70% of all neonatal mortality and morbidity, and represents one of the highest costs per patient in health care budgets. Even though survival of preterm infants has increased due to the development of neonatal intensive care units, there has been no decrease in the rate of premature birth in the past 30Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.061200. ABBREVIATIONS:OT, oxytocin; AVP, arginine vasopressin; OTR, oxytocin receptor; SSR126768A, 4-chloro ; ANOVA, analysis of variance; IUP, intrauterine pressure.

Oxytocin antagonists may improve infertility treatment

“…Administration of oxytocin that stimulated uterine PGF 2a expression was shown to decrease both endometrial blood supply and embryonic survival in cattle (17). Oxytocin receptor blockade, apart from the reduction of uterine contractions, is reported to inhibit the stimulation of uterine production of prostaglandins (18).…”

Effect of atosiban on rabbit embryo development and human sperm motility

“…Atosiban may effectively decrease the contractile activity of the nonpregnant uterus, and in addition, oxytocin antagonism has been shown to decrease PGF 2a formation (30) and increase uterine perfusion (31). Such a multidirectional mode of action may be of benefit in comparison to other tocolytic agents such as piroxicam (cyclooxygenase inhibitor) or ritodrine (beta-2 adrenoreceptor agonist).…”

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

“…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.…”