Lipophilicity-controlled optimization delivers PERK inhibitor APL-11056
- Starting from a literature-derived PERK inhibitor of moderate potency but good kinase selectivity and PK, the team ran a lead optimization campaign steered by log D and lipophilic ligand efficiency.
- This produced APL-11056 (compound 49), a potent and selective PERK inhibitor with excellent in vivo pharmacokinetics.
- High permeability is linked to a fluorine alpha to the core benzamide, which appears to limit efflux-transporter recognition.
💡 Points
Letting LLE drive the SAR instead of chasing potency is the discipline that makes this readable, and the alpha-fluoro benzamide trick for dodging efflux is a handy one for my own amide series. PERK's ISR biology has bitten inhibitors before, so the tolerability data will matter more than the PK table.