Oxytocin pharmacokinetics

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. 

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

Preterm labour is the major cause of perinatal morbidity and mortality. Oxytocin antagonists offer an attractive approach to prevention. Chapter 7 reviews three decades of medicinal chemistry in this field. The peptide approach has resulted in valuable injectable products. Selectivity over the related vasopressin receptors and improvement in pharmacokinetic profile have been the key challenges for more recent non-peptide programmes, and these seem likely to yield orally available medicines. 

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]. 

Borthwick AD, Davies DE, Exall AM, Hatley RJD, Hughes JA, Irving WR, Livermore DG, Sollis SL, Nerozzi F, Valko KL, Allen MJ, Perren M, Shabbir SS, Woollard PM, Price MA (2006) 2, 5-Diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency. J Med Chem 49(14) 4159-4170... 

Pharmacokinetics Oxytocin is distributed throughout the extracellular fluid and is eliminated with a half-life of 3 to 5 minutes. 

Two possible explanations of this situation come to mind. Either, there is some as yet unrecognised enzyme or enzyme system to which oxytocin, its deamino-analogues, and the carba-analogues are all equally susceptible (e. g,, an endopeptidase or amidase) and which plays a decisive role in the overall inactivation or, the invariance of the time course of the response is the result of some particular pharmacokinetic situation which makes this time course independent of the enzymic inactivation of the hormone. 

L., Allen, M. J., Woollard, P. M., Pullen, M. A., Westfall, T. D., Stanislaus, D. J. (2012). Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists synthesis, pharmacokinetics, and in vivo potency. Journal of Medicinal Chemistry, 55, 783-796. 

However, compounds of the type 89 were reported to have low solubility and relatively high log D. This resulted in replacement of the 3,4-difluorobenzaldehyde with 2-methyloxazole-4-aldehyde in the U-4CR. Compound 92 (GSJC221149A) has been noted to have nanomolar affinity for the oxytocin receptor with > 1400-fold selectivity over the closely related vasopressin receptors. Compound 92 (Figure 7.3) has also shown to have a good rat pharmacokinetic profile and low human microsomal clearance and inhibits oxytocin-induced contraction in vivo in the anesthetized rat... 

---