Peptide antagonists

2.1.1. Atosiban

Atosiban 2 is the only oxytocin antagonist approved for the acute treatment of preterm labour. It is a cyclic peptide based on the natural hormone oxytocin. Early work established that modifications of the endogenous agonist oxytocin like capping of the 2-tyrosine hydroxyl group as a methyl or ethyl ether led to potent peptide antagonists [11]. The desamino ethoxy analogue was further modified at the 4th and 8th position by Ferring Laboratories [12] to give atosiban 2, [1-deamino-D-2-Tyr(OEt)-4-Thr-8-Orn] -oxytocin. It is a mixed oxytocin/vasopressin V1a antagonist. In human recombinant receptors in vitro, atosiban had a K of 397 nM at the OT receptor and 4.7 nM at the V1a receptor, and low affinity at the V1b (K = 256 nM) and V2 (K = 3195 nM) receptors [13]. Atosiban is administered as an initial bolus followed by a continuous high-dose infusion over 3 h, then a lower dose continuous infusion for up to 45 hours.

Clinical experience with this compound, has attested to its effectiveness in at-risk patients [14,15]. Atosiban was reviewed in 2004 [7]; since then several studies have been conducted comparing the efficacy and safety profile of atosiban as a tocolytic agent (a medication that arrests uterine contractions in preterm labour) to that of p-adrenergic agonists. All conclude that atosiban has a similar efficacy and a lower incidence of adverse effects, particularly those of a cardiovascular nature [16].

2.1.2. Barusiban

Although atosiban can be used to delay imminent preterm birth between 24 and 33 weeks of gestational age, it has a short duration of action and has to be dosed as a continuous infusion. In addition, atosiban is a mixed oxytocin/vasopressin Via antagonist, being more potent at the vasopressin Via receptor than at the OT receptor. In order to address the issues of short duration of action and lack of selectivity for the OT receptor over the vasopressin receptor seen with atosiban, further optimization of the OT nonapeptide template has been investigated. The disulphide bridge of des-amino-oxytocin was replaced with a methylene sulphide unit in an effort to enhance the biological half-life. In addition 2nd, 4th and 6th positions on the six-membered cyclopeptide ring were modified as well as the three amino acids that extend from the 6th position which substantially shortened the exocyclic chain. The resulting barusi-ban 3 (FE 200440) showed improved oxytocin antagonist potency. It is 36-fold more potent than atosiban at the human cloned OT receptor with a K = 0.31 nM and 275fold more selective for the human OT receptor (hOTR) versus the human vasopressin Via receptor (hVia) unlike atosiban which is 26-fold more selective for the hVia receptor [17]. Barusiban was ~100 times more potent than atosiban at inhibiting oxytocin-induced contractions of the myometrium from preterm and term pregnant women [18]. In a preclinical study, barusiban 3 had a much longer duration of action (> 13-15 h, compared with 1-3 h for atosiban) in the cynomolgus monkey model of preterm labour [19] where it was also four times more potent than atosiban.

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