Discovery of novel 3-Benzyloxyaminopyridines as orally available and intracranially active selective ROS1 inhibitors...

The selectivity, central nervous system progression and drug-resistant mutations have raised significant concerns regarding the effectiveness of ROS1 inhibitors. Novel entities have been designed through precise molecular simulation. Introducing larger biphenyl groups in the hydrophobic region enhances ROS1 selectivity and improves lipid solubility for better blood-brain barrier penetration. Further reducing steric collision in the solvent region, compound stability is improved against the ROS1^G2032R mutation. The preferred compound SMU-037 demonstrates nanomolar inhibition against the ROS1 enzyme and approximately 25-fold selectivity over ALK. Moreover, SMU-037 exhibits a 20- to 100-fold improvement in potency for inhibiting the ROS1^G2032R mutation compared to Lorlatinib and Crizotinib, with desired bioavailability (F = 62.4 %). Additionally, SMU-037 effectively suppresses tumor progression in both xenograft and intracranial models, exhibiting enhanced penetration into the central nervous system and resulting in a substantial reduction of brain lesions. These findings suggest that SMU-037 is a selective ROS1 inhibitor with superior sensitivity against the G2032R mutation and significant intracranial potency.