HEP-50768 is an orally active and selective MRGPRX4 ( hX4 ) antagonist. HEP-50768 suppresses basal and bile-acid-stimulated hX4 activity. HEP-50768 binds the receptor’s transmembrane pocket and induces extracellular loop rearrangements. HEP-50768 modulates GPCR microswitch motifs and reduces bile-acid-induced pruritic scratching behaviors. HEP-50768 can be used for the research of cholestatic pruritus [1].
In Vivo, HEP-50768 (5-10 mg/kg; p.o.; single dose; 2.5 hours before pruritus induction) significantly reduces DCA-3S-induced scratching behavior in hX4-humanized rats, demonstrating potent antipruritic efficacy[1].
In Vitro, HEP-50768 (1 nM-1 μM; 30 min) potently inhibits DCA-induced calcium mobilization in HEK293T cells stably expressing hX4 with an IC50 of 14 nM and achieves 100% inhibition at 2 μM[1]. HEP-50768 (0.1 μM) acts as an inverse agonist, significantly reducing basal inositol monophosphate levels in HEK293T cells expressing hX4[1]. HEP-50768 (2 μM; 1.5 h) modestly reduces GTPase activity of the purified hX4-Gq complex, consistent with its inverse agonist activity[1]. HEP-50768 (0.02-50 nM) binds purified apo hX4 and hX4-miniGαq complex with high, comparable affinity, exhibiting K0 values of 0.6 nM and 0.7 nM, respectively[1]. HEP-50768 (0.1 nM-10 mM; 30 min) is highly selective for hX4, showing weak inhibition of hX1 (IC50 = 16 μM) and hX2 (IC50 = 1.5 μM) with no agonist activity against either receptor[1]. HEP-50768 (~5 min) shows minimal hERG channel inhibition in HEK293 cells stably expressing hERG, with an IC50 exceeding 30 μM[1].
References:
[1]. Yang J, et al. Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment. Nat Chem Biol. Published online April 9, 2026.
In Vivo, HEP-50768 (5-10 mg/kg; p.o.; single dose; 2.5 hours before pruritus induction) significantly reduces DCA-3S-induced scratching behavior in hX4-humanized rats, demonstrating potent antipruritic efficacy[1].
In Vitro, HEP-50768 (1 nM-1 μM; 30 min) potently inhibits DCA-induced calcium mobilization in HEK293T cells stably expressing hX4 with an IC50 of 14 nM and achieves 100% inhibition at 2 μM[1]. HEP-50768 (0.1 μM) acts as an inverse agonist, significantly reducing basal inositol monophosphate levels in HEK293T cells expressing hX4[1]. HEP-50768 (2 μM; 1.5 h) modestly reduces GTPase activity of the purified hX4-Gq complex, consistent with its inverse agonist activity[1]. HEP-50768 (0.02-50 nM) binds purified apo hX4 and hX4-miniGαq complex with high, comparable affinity, exhibiting K0 values of 0.6 nM and 0.7 nM, respectively[1]. HEP-50768 (0.1 nM-10 mM; 30 min) is highly selective for hX4, showing weak inhibition of hX1 (IC50 = 16 μM) and hX2 (IC50 = 1.5 μM) with no agonist activity against either receptor[1]. HEP-50768 (~5 min) shows minimal hERG channel inhibition in HEK293 cells stably expressing hERG, with an IC50 exceeding 30 μM[1].
References:
[1]. Yang J, et al. Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment. Nat Chem Biol. Published online April 9, 2026.