Discovery of MP-4222, a potent small molecule antagonist of gastrin-releasing peptide receptor for the treatment of pruritus | Poster Board #329

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 IC₅₀ of 21.2 nM (4.3× improvement from PD 176252) and functional IC₅₀ 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.