D17(Shanghai Institute of Materia Medica)

To meet the clinical need for therapeutic efficacy against cognitive impairment and pain comorbidities in depression, a rational drug design approach was used in the current study to synthesize a series of spirocyclic diamine derivatives. Among them, (R)-D24 exhibited triple monoamine reuptake inhibitory activity (SERT, NET, and DAT), while D6 and D17 showed potent inhibitory activity against both SERT and 5-HT_3AR. D6 and D17 have acceptable systemic exposure and oral bioavailability in mice and low clearance in human liver microsomes. D6 and D17 exhibited favorable safety profiles in hepatic, renal, and hERG toxicity assays and showed potent antidepressant-like effects in the forced swim test, supporting their potential for further preclinical investigation. In addition, the compound-target interactions of the key compounds were analyzed through molecular docking. These results highlight the rationality of our design and provide new perspectives for the development of antidepressant drugs.