Structure-Guided RXFP4 Agonists Stay in the Gut and Ease Constipation in Mice
- Guided by the cryo-EM structure of RXFP4, the authors built a tetrahydroisoquinoline agonist series aimed at two hurdles: close homology to RXFP3 and the need for gut-restricted exposure.
- Lead compound 44 was a potent agonist with strong selectivity over RXFP3 and a pharmacokinetic profile heavily skewed toward ileum over plasma.
- Oral dosing was effective in a loperamide-induced constipation mouse model.
💡 Points
Getting a small molecule onto a peptide-GPCR whose paralog looks nearly identical is the hard part, and using the cryo-EM structure to buy RXFP3 selectivity is the right play. The gut-over-plasma skew is what I'd look at first, since a locally acting agonist sidesteps systemic liabilities. I'd still want permeability, efflux and metabolic stability data behind that ileum exposure.