ALDH1B1 inhibitor IGUANA-5 fixes metabolic and efflux liabilities
- SAR work on a guanidine-based ALDH1B1 inhibitor series explored the core, the catalytic-site aryl ring and the biaryl group.
- Earlier compounds proved metabolically unstable and were pumped out of intestinal epithelial cells.
- Replacing the biaryl and altering the core gave an aryl-alkyl ether, IGUANA-5, which inhibits colon and pancreatic cancer spheroid growth and shows improved in vitro and in vivo pharmacology.
💡 Points Based on the abstract
Is the ADME fix real or just cosmetic? Swapping the biaryl for an aryl-alkyl ether is a cheap, tractable change that tackles both metabolic lability and efflux, which is the right diagnosis for a guanidine series. I'd want isoform selectivity against ALDH1A1/ALDH2 and permeability data before trusting the spheroid readout.