Retosiban (GSK-221149A): A Comprehensive Monograph on a Functionally Selective Oxytocin Receptor Antagonist

Executive Summary

Retosiban (GSK-221149A) is an investigational, orally active, small molecule developed by GlaxoSmithKline (GSK) as a potential treatment for spontaneous preterm labor (sPTL).[1] It represents a significant advancement in the field of tocolytic therapy, designed specifically as a potent and highly selective antagonist of the human oxytocin receptor (OTR).[3] The compound is distinguished by its sub-nanomolar binding affinity ($K_i = 0.65$ nM) and exceptional selectivity of over 1400-fold for the OTR compared to the structurally related vasopressin receptors, a key feature intended to minimize off-target effects.[1]

The primary pharmacological innovation of Retosiban lies in its functionally selective mechanism of action. Unlike the first-generation peptide antagonist Atosiban, which exhibits partial agonist activity on the Gαi signaling pathway, Retosiban acts as a "clean" competitive antagonist and inverse agonist on the Gαq pathway without engaging Gαi-mediated signaling. This design was intended to prevent the downstream production of pro-contractile prostaglandins, a potential liability of Atosiban therapy.[5]