Epelsiban (INN,[1] USAN,[2] code name GSK-557,296-B) is an orally bioavailable drug which acts as a selective and potent oxytocin receptor antagonist (Ki = 0.13 nM).

[8] Screening the GSK compound collection and various libraries identified 2,5-diketopiperazines (2,5-DKPs) exemplified by 1 as novel and selective antagonists at the human oxytocin receptor (OTR).

Initial structure–activity relationship (SAR) studies led to the semi-rigid and chirally pure 2,5-DKP 2 (Ki = 4nM), with cis disposed substituents at C-3 and C-6 and the R side-chain configuration at C-7.

[5] As expected, despite this success achieved in mice, oral epelsiban in humans at 50 or 150 mg has not shown satisfactory results in a double blind, placebo-controlled trial.

In the highly stereoselective synthesis of Epelsiban 11, the linear peptide 8 is formed by the four-component Ugi reaction of the carboxybenzyl (Cbz) protected R-indanylglycine 4, D-alloisoleucine methyl ester hydrochloride 5, 2,6-dimethylpyridine-3-carboxaldehyde 6 and 2-benzyloxyphenylisonitrile 7.

Hydrogenation to remove the Cbz and benzyl protecting groups, enabled cyclization of the linear peptide 8 to occur to give the phenolic cyclic dipeptide 9.

This was to decrease the risk that templates would be chosen that would cross the blood brain barrier and thus block the central effects of oxytocin both in the foetus and in the mother.

This identified the small, conformationally constrained, homochiral 2,5-DKP scaffold as the preferred template and lead to the success in designing and developing the highly potent and selective, orally active, peripheral oxytocin antagonist Epelsiban as a clinical candidate.