Hot Topics: Neurokinin 3 receptor antagonism for menopausal hot flushes

Neurokinin B signalling is increased in menopausal women and has been implicated as an important mediator of hot flushes. A phase 2 trial has assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901). Results showed it safely and effectively relieved hot flush. The finding that pharmacological blockade of NKB signalling with an oral NK3R antagonist can significantly improve symptoms independently of any hormonal effect fits with the pre-existing data, and indicates promise for such agents. However, larger scale studies of longer duration are needed. Since this condition affects 70% of menopausal women ( i.e. ~ 10 million in the UK) this publication was covered widely in the press, for example in the UK Daily Telegraph with “Could this drug be the key to stopping hot flushes for menopause sufferers?”. Partly as a consequence of press coverage, the paper garnered an impressive Altmetric score of 296 (that will notch up by at least one from this posting).

Our GtoPdb ligand entry shows a number of aspects related to repurposing and data linking problems associated with multiple synonyms for the same structure in multiple clinical contexts. With its original designation as AZD2624 it was on the AZ Open Innovation Clinical Compound Bank repurposing proposal list (but has now been withdrawn) since it failed in its originally tested indication for schizophrenia (PMID 24525659). Unusually, there is no primary publication on the medicinal chemistry but we were able to get the NK3R in vitro binding data from the NCATs AZD2624 data sheet. It was renamed to AZD4901 for the new indication of Polycystic ovary syndrome (PCOS) but was again not progressed (PMID 27459523). In the meantime WO2015033163 was filed by Imperial Innovations for the use of AZD2624 for the treatment of hot flushes. By 2016 rights had been acquired by Millendo where the structure was renamed MLE4901 for the indications of PCOS and vasomotor symptoms (VMS).

Prague et al. (2017). Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet, S0140-6736(17)30823-1. [PMID: 28385352]

The ligand entry was updated in our 2017.3 release. When it gets submitted to PubChem it may be the only source that connects the one structure to its three synonyms and cross-references the publications and clinical trials for the different therapeutic investigations

Comments by Chris Southan (@cdsouthan)

Posted in Hot Topics

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