Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment - PubMed
3 hours ago
- #MRGPRX4
- #inverse agonist
- #cholestatic itch
- Chronic itch in cholestatic and uremic conditions lacks adequate treatments, with MRGPRX4 identified as a key mediator.
- HEP-50768 is a potent and selective small-molecule inverse agonist of MRGPRX4, developed through screening and optimization.
- Cryo-electron microscopy revealed the unique binding mode and inhibitory mechanism of HEP-50768.
- In hX4-humanized rats, HEP-50768 effectively suppressed bile-acid-induced itch behaviors.
- Preclinical studies in rats and monkeys showed promising absorption, distribution, metabolism, excretion, and safety profiles.
- HEP-50768 is a viable therapeutic candidate for chronic itch, advancing toward clinical evaluation.