Preterm Labour: An Overview of Current and Emerging Therapeutics

Abstract

Preterm labour is a major cause of perinatal mortality and morbidity. However, during the past 40 years of clinical studies and despite the use of multiple therapeutic agents, the rate of preterm birth has not drastically declined. In 1991, it was estimated that in the US approximately 116,000 women admitted with acute episodes of preterm labour were treated each year with ritodrine, which is the first drug approved by the US FDA and still remains the standard therapy for treating preterm labour. Ritodrine (Yutopar( trade mark )) stimulates the beta(2)-adrenergic receptor throughout the body, causing an inhibitory action in different tissues that, among other side effects, also leads to an attenuation of uterine contractility. More recently, a new therapeutic agent, atosiban (Tractocile( trade mark )), a peptidic oxytocin receptor antagonist, has been introduced to the market. However, the use of the various pharmacological agents to treat preterm labour remains restricted, due to lack of uterine selectivity, low efficacy and potentially serious side effects for the mother or the foetus. Therefore, there is an urgent need to develop drugs with myometrial selectivity that would allow long-lasting inhibition of labour and prolong pregnancy up to a stage when good foetal maturation raises the chances of survival. One of the major obstacles hampering the development of new therapeutic agents is the marked inter-species difference in terms of preterm labour physiology, which complicates the preclinical evaluation of new candidate molecules in animal models of disease. In this review, the authors will provide a comprehensive update of past, current and new approaches for the management of preterm labour, including beta(2)-adrenergic agonists, calcium channel blockers, oxytocin antagonists, prostaglandin antagonists and other potential therapeutics. For each of the therapies used today, the review will cover the mechanism of action, benefit and adverse effects, and discuss the promise and potential benefits of new emerging therapeutic agents.

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists

“…Henceforth, to confirm the previous statement, we performed the linear regressions on the dataset after removing all those compounds, which contain rigid derivatives: 14,15,16,19,20,21,22,30,43,44,45,46, 50, 51, 57 and 58 (Tables 7-9; Fig. 2).…”

“…[13]. The molecules that competitively inhibit the interaction of OT with its membrane receptor have been of some interest because of their potential use in the treatment of preterm labour [14]. In case of the human oxytocin receptor and agonist/antagonist binding the peptide molecules bind to the core, exracellular loops and N-terminal regions of the human OTR (hOTR) [15,16].…”

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

“…Atosiban, an OT/AVP peptide receptor antagonist, recently launched in Europe, and ␤ 2 -adrenergic agonists, such as Ritodrine, are the only licensed tocolytic agents. However, the former is a peptide molecule to be administered parenterally and is a more potent V 1a than OT receptor antagonist in humans, and the latter has been associated with severe maternal and fetal (mainly cardiovascular) adverse effects and tachyphylaxis (Goodwin and Zograbyan, 1998;Vatish and Thornton, 2002;Schwarz and Page, 2003).…”

Small Molecule Drug Discovery in the Fast-Changing World of Biotechnology

“…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. Given its biological function, the OT-R has long been recognized as a prime pharmacological tar-get for the treatment of preterm labor, a condition often leading to premature birth, which remains a major problem in obstetrics affecting about 10% of all births, making it the largest cause of perinatal morbidity and mortality [16]. Proof of concept comes from the peptide OT-R antagonist Atosiban, marketed in Europe under the trade name of Tractocile, which was shown to be efficacious in the treatment of imminent preterm birth.…”