Oxytocin antagonists

Thornton S, Vatish M, Slater D (2001) Oxytocin antagonists clinical and scientific considerations. Exp Physiol 86 297-302... 

Oxytocin Antagonists as Potential Therapeutic Agents for the Treatment of Preterm Labour... 

TREATMENT OF PRETERM LABOUR The Role of Oxytocin in Labour Regulation of Oxytocin during Labour Regulation of the Oxytocin Receptor Experiences with Oxytocin Antagonists Selective OT or Mixed OT/Via Blockade ... 

METHODS USED TO MEASURE OXYTOCIN ANTAGONIST ACTIVITY Competition Binding... 

More recently, a novel form of therapy in the form of oxytocin antagonists has become available. Though currently only an intravenous formulation for acute therapy is available in Europe (but not in the US), this class of drugs offers hope for a more effective treatment for preterm labour. 

Nearly all the clinical data comes from the use of atosiban (see Peptide Antagonists), a peptide oxytocin antagonist that is licensed in Europe for acute (48 h) treatment of preterm labour. Early clinical studies demonstrated the ability of atosiban to inhibit uterine contractions associated with labour [14]. Following these successful phase II trials, full phase III trials were... 

One compound from this series, (10), has been tested in vitro in human myometrium tissue obtained at term following caesarean section and shown to inhibit contractions induced by oxytocin [44] with a pA2 of 7.6. This is one of the first direct indications that the use of an oxytocin antagonist may be of benefit in the treatment of preterm labour in humans. This compound has been extensively studied in the near-term baboon and has been shown to inhibit nocturnal and near-term contractions following an intravenous bolus injection [45]. Further studies on the effect of oxytocin antagonism in the weeks leading up to delivery in the baboon have also been published [46]. 

Recently, introduction of a 4-sulphur atom into the spirocyclohexane ring has been reported, along with replacement of 6-Cys with the more constrained penicillamine to give potent oxytocin antagonists, e.g. (11) [47, 48],... 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Table 7.2 BINDING AFFINITIES OF SPIROPIPERIDINE OXYTOCIN ANTAGONISTS...

Work on this series of non-peptide oxytocin antagonists was then terminated at Merck, in favour of a promising new template. Binding affinity data for key compounds in this new series are summarised in Table 7.3. Some years ago, dihydroquinolinones such as OPC-21268, (28), had been disclosed as vasopressin Vi antagonists. This compound underwent clinical evaluation by Otsuka for hypertension and cardiac failure [76], but was... 

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