Retosiban

• CAT Number: I009015
• CAS Number: 820957-38-8
• Molecular Formula: C27H34N4O5
• Molecular Weight: 494.592
• Purity: ≥95%
• Synonyms: GSK221149A; GSK 221149A; GSK-221149A; GSK221149; GSK 221149; GSK-221149; GSK221,149; GSK 221,149; GSK-221,149; Retosiban;(3R,6R)-6-((2S)-Butan-2-yl)-3-(2,3-dihydro-1H-inden-2-yl)-1-((1R)-1-(2-methyl- 1,3-oxazol-4-yl)-2-(morpholin-4-yl)-2-oxoethyl)pip
• Target: Oxytocin Receptor
• Solubility: Soluble in DMSO, not in water
• Storage: 0 - 4 °C for short term, or -20 °C for long term
• IUPAC Name: (3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione
• InChI: InChI=1S/C27H34N4O5/c1-4-16(2)23-25(32)29-22(20-13-18-7-5-6-8-19(18)14-20)26(33)31(23)24(21-15-36-17(3)28-21)27(34)30-9-11-35-12-10-30/h5-8,15-16,20,22-24H,4,9-14H2,1-3H3,(H,29,32)/t16-,22+,23+,24+/m0/s1
• InChIKey: PLVGDGRBPMVYPB-FDUHJNRSSA-N
• SMILES: CCC(C)C1C(=O)NC(C(=O)N1C(C2=COC(=N2)C)C(=O)N3CCOCC3)C4CC5=CC=CC=C5C4

Retosiban(CAT: I009015), also known as GSK-221,149-A; is an orally active, potent and selective, sub-nanomolar (Ki = 0.65 nM) oxytocin receptor antagonist with >1400-fold selectivity over the related vasopressin receptors. Retosiban inhibits the pro contractile effect of stretch on human myometrium. Retosiban prevented stretch-induced stimulation of human myometrial contractility. Retosiban treatment is a potential approach for preventing preterm birth in multiple pregnancies. Retosiban is under phase III developed by GlaxoSmithKline for the treatment of preterm labour.

Overview of Clinical Research

Originator: GlaxoSmithKline
Class: Indenes; Morpholines; Oxazoles; Piperazines; Small molecules; Tocolytics
Mechanism of Action: Oxytocin receptor antagonists
Orphan Drug Status: No

New Molecular Entity: Yes


Highest Development Phases: Phase III Preterm labour

Reference

1. Endocrinology. 2015 Oct;156(10):3511-6. doi: 10.1210/en.2015-1378. Epub 2015 Jul
24.

The Effect of an Oxytocin Receptor Antagonist (Retosiban, GSK221149A) on the
Response of Human Myometrial Explants to Prolonged Mechanical Stretch.

Moraitis AA(1), Cordeaux Y(1), Charnock-Jones DS(1), Smith GC(1).

Author information:
(1)Department of Obstetrics and Gynaecology, University of Cambridge, National
Institute for Health Research Cambridge Comprehensive Biomedical Research Centre,
CB2 2SW, United Kingdom.

Multiple pregnancy is a major cause of spontaneous preterm birth, which is
related to uterine overdistention. The objective of this study was to determine
whether an oxytocin receptor antagonist, retosiban (GSK221149A), inhibited the
procontractile effect of stretch on human myometrium. Myometrial biopsies were
obtained at term planned cesarean delivery (n = 12). Each biopsy specimen was
dissected into 8 strips that were exposed in pairs to low or high stretch (0.6 or
2.4 g) in the presence of retosiban (1 μM) or vehicle (dimethylsulfoxide) for 24
hours. Subsequently, we analyzed the contractile responses to KCl and oxytocin in
the absence of retosiban. We found that incubation under high stretch in vehicle
alone increased the response of myometrial explants to both KCl (P = .007) and
oxytocin (P = .01). However, there was no statistically significant effect of
stretch when explants were incubated with retosiban (P = .3 and .2,
respectively). Incubation with retosiban in low stretch had no statistically
significant effect on the response to either KCl or oxytocin (P = .8 and >.9,
respectively). Incubation with retosiban in high stretch resulted in a
statistically significant reduction (median fold change, interquartile range, P)
in the response to both KCl (0.74, 0.60-1.03, P = .046) and oxytocin (0.71,
0.53-0.91, P = .008). The greater the effect of stretch on explants from a given
patient, the greater was the inhibitory effect of retosiban (r = -0.65, P = .02
for KCl and r= -0.73, P = .007 for oxytocin). These results suggest that
retosiban prevented stretch-induced stimulation of human myometrial
contractility. Retosiban treatment is a potential approach for preventing preterm
birth in multiple pregnancy.

2. Bioorg Med Chem Lett. 2008 Jan 1;18(1):90-4. Epub 2007 Nov 6.

The discovery of GSK221149A: a potent and selective oxytocin antagonist.

Liddle J(1), Allen MJ, Borthwick AD, Brooks DP, Davies DE, Edwards RM, Exall AM,
Hamlett C, Irving WR, Mason AM, McCafferty GP, Nerozzi F, Peace S, Philp J,
Pollard D, Pullen MA, Shabbir SS, Sollis SL, Westfall TD, Woollard PM, Wu C,
Hickey DM.

Author information:
(1)Department of Medicinal Chemistry, GlaxoSmithKline Research and Development,
Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK.


Optimisation of a series of oxazole diketopiperazines has led to the discovery of
a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been
shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.