Property-Based Design of Xanthine Derivatives as Potent and Orally Available TRPC4/5 Inhibitors for Depression and Anxiety

Transient receptor potential canonical channels 4 and 5 (TRPC4/5) are nonselective cation channels involved in emotional regulation, positioning them to be promising targets for treating mental disorders such as anxiety and depression. HC-070, a potent TRPC4/5 inhibitor, exhibits significant anxiolytic and antidepressant effects in animal models, though its drug-like properties require optimization. In this study, we applied a property-based drug design (PBDD) approach to optimize HC-070, leading to the discovery of compound <b>32</b>, which shows improved LipE and Fsp3 values, reduced hERG blocking activity, enhanced metabolic stability, increased aqueous solubility, and superior oral bioavailability. Oral administration of compound <b>32</b> in mouse models demonstrates anxiolytic and antidepressant efficacy comparable to fluoxetine. This study supports the therapeutic potential of TRPC4/5 inhibitors for mental disorders and identifies compound <b>32</b> as a promising candidate for further investigation. Furthermore, our work underscores the value of PBDD in optimizing lead compounds during drug discovery process.