Oxazole-Based Ferroptosis Inhibitors with Promising Properties to Treat Central Nervous System Diseases
Camilla Scarpellini, Greta Klejborowska, Caroline Lanthier, Ariane Toye, Karolina Musiałek, Emily Van San, Magali Walravens, Maya Berg, Behrouz Hassannia, Pieter Van der Veken, Hans De Winter, Tom Vanden Berghe, Koen Augustyns
Abstract
Ferroptosis plays an important role in the occurrence and development of many diseases, including neurodegenerative diseases. Thus, ferroptosis inhibitors able to cross the blood-brain barrier may have therapeutic potential. The best ferroptosis inhibitors so far are lipophilic radical trapping antioxidants (RTAs) that block lipid peroxidation in membranes. Several generations of ferrostatins have been synthesized, among which UAMC-3203 showed high potency in animal models with improved properties compared to ferrostatin-1. To further improve its pharmacokinetics properties, drug-likeness, and permeability, we modified UAMC-3203 by decreasing the size of the molecule and reducing its polarity by replacing the sulfonamide first by amide groups and subsequently by isosteric oxazoles. Herein, we present the design, synthesis, and biological evaluation of a novel series of oxazole RTAs with high potency, excellent oral bioavailability, and high concentrations in brain tissue.