The incidence of pruritus in the US is estimated to affect up to 20% of all adults. To date, FDA has only approved one mechanism-based anti-pruritic drug, the Korsuva (difelikefalin) Injection for moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP). The unmet medical need remains significant. We identified the gastrin-releasing peptide receptor (GRPR) as a pruritus biomarker. We performed structure-activity studies starting from a known GRPR small molecule antagonist, PD 176252. We improved the binding affinity, antagonistic functional potency, and removed potentially unfavorable functionalities. Our new lead compound MP-4222 has binding IC<sub>50</sub> of 21.2 nM (4.3× improvement from PD 176252) and functional IC<sub>50</sub> of 18.5 nM (1.1× improvement from PD 176252). PD 176252 is a potent dual antagonist of GRPR and neuromedin B receptor (NMBR), and 4-fold more potent against NMBR over GRPR in our functional assay. MP-4222 is a balanced dual antagonist with an improved the GRPR/NMBR ratio of 1. MP-4222 significantly reduced itching behavior in mouse models.

Discovery of MP-4222, a potent small molecule antagonist of gastrin-releasing peptide receptor for the treatment of pruritus

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.