Antagonist potencies, oxytocin

Table 2.15 Oxytocin (OT) Analogs with Antagonistic Potencies at the Rat Uterus In Vitro...

The IC50 is similar to AD50 or ID50 experiments, except that plasma concentration of the antagonist is measured during the experiment and the potency is expressed as the plasma concentration of the antagonist causing 50% inhibition of the oxytocin response. 

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... 

Similarly, though plasma protein binding data were not ostensibly used in the identification of an oxytocin antagonist suitable for advancement to the clinic, such data were used to explain the differences between in vivo and in vitro potency [46]. 

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... 

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. 

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