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 32, 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 32 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 32 as a promising candidate for further investigation. Furthermore, our work underscores the value of PBDD in optimizing lead compounds during drug discovery process.