Oxytocin-receptor antagonists

This scaffold recently gained high attention since compound GSK-221149A currently underwent advanced clinical trials as an oxytocin receptor antagonist... 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

Leach CA, Liddle J, Peace S, Philp J, Smith lED, Terrell LR, Zhang J (2006) Preparation of l,6-disubstituted-(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-2,5-piperazinedione derivatives as oxytocin receptor antagonists for the treatment of pre-term labor, dysmenorrhea and endometriosis. PCT Int Appl WO 2006067462 Al 20060629... 

Borthwick AD, Hickey DMB, Liddle J, Mason AM (2006) Preparation of diketopiperazines as oxytocin receptor antagonists. 2005-EP6760 W02006000399, 20050621... 

A recent Cochrane review failed to demonstrate the advantage of oxytocin receptor antagonists for women with preterm labour as a form of tocolytic therapy. Possible side effects are nausea, vomiting and headache in the mother. Oxytocin receptor antagonists for preterm labour do not improve infant outcomes more than placebo or other tocolytics. 

Papatsonis D, Flenady V, Cole S, LUey H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2005. Issue 3. 

Fig. 3A, B Neuropeptide effects on anxiety-related behavioiu. A The oxytocin receptor antagonist (black bars) administered intracerebroventricularly (i.c.v.) increased indices of anxiety-related behaviour in pregnant rats as measured on the elevated plus maze. Entries into the closed arms indicate unchanged locomotor activity. B Prolactin is an anxiolytic neuropeptide in female rats as revealed by i.c.v. administration of synthetic prolactin (grey and black bars represent two different doses) and by antisense targeting of the prolactin receptor (R). Vehicle (white bars) vs mixed bases (grey bars) and antisense oligodeoxynu-cleotide (black bars). p<0.05 vs vehicle (white bars). (Adapted from Nemnann et al. 2000) and Torner et al. 2001)...

Comparative substructural elements of peptide and nonpeptide ligands examples of oxytocin receptor antagonists and HIV protease inhibitors... 

The decarboxylation of diacyl peroxides was also used in the synthesis of a nonapeptide 148 and 5-methyl L-arginine 151 (Scheme 2.35) [65,66]. The peptide 148 is an analogue of an oxytocin receptor antagonist. The photolysis of precursor 146 gave 34% of product 147, which was reprotected with Fmoc and then incorporated into the oligopeptide. 5-Methyl arginine 151 was synthesized as a probe to study the nitric oxide synthase (NOS) active site and mechanism. The photolysis of 149 gave 150... 

Atosiban, an oxytocin receptor antagonist, is also licensed for treatment of premature labour. This drug has fewer side effects than the / -agonists and is particularly useful if the mother has cardiac disease, because intravenous 2-agonists can cause adverse cardiac actions in the mother. 

If labour begins prematurely, before 33 weeks gestation, myometrial relax-ants (tocolytic agents) can delay it for 48 hours. Beta-2-agonists, such as ritodrine hydrochloride, are given for up to 48 hours to elicit relaxation. Longer treatment is not recommended, because of risk of adverse effects on the mother. Nifedipine and the oxytocin receptor antagonist atosiban are also used to reduce premature uterine contractile activity. 

Oxytocin Receptor Antagonists Because labor is mediated by increasing release of oxytocin from the posterior pituitary, it was thought that the oxytocin receptor antagonists (Antociban ) would become the leading tocolytic drugs. This has not been borne out by clinical... 

B.K. Matuszewski, C.M. Chavez-Eng, M.L. ConstsmzeT, Development of LC-MS-AdS methods for the determination of a new oxytocin receptor antagonist (L-368,899) extracted from human plasma and urine a case of lack of specificity due to the presence of metabolites, J. Chromatogr. B, 716 (1998) 195. 

SCHEME 13,2 Synthesis of oxytocin receptor antagonists using O-benzyloxy phenyl isocyanide (li) in the U-4CR. 

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