N-aryl-N-acyl diamine derivatives as novel selective serotonin/norepinephrine transporter inhibitors for the treatment of premature ejaculation

The distinct roles of monoamine neurotransmitters in ejaculation highlight that selective inhibition of SERT and NET, while preserving DAT activity, emerges as a potential targeted therapeutic strategy for premature ejaculation. In this study, a series of inhibitors based on an N-aryl-N-acyl diamine scaffold were designed and evaluated for their anti-PE potential through both in vitro and in vivo assays. Among these N-aryl-N-acyl diamine derivatives, compound 7 exhibited potent dual SERT/NET activity (IC₅₀(SERT) = 11.2 nM, IC₅₀(NET) = 32.0 nM) with limited DAT activity (IC₅₀(DAT) > 20 μM). Pharmacokinetic studies revealed that compound 7 exhibited favorable metabolic stability in microsomes and acceptable oral brain exposure in rats. Safety assessments demonstrated a favorable safety profile for compound 7. In vivo efficacy evaluation showed that a single dose of compound 7 (20 mg/kg, i. p.) significantly alleviated PE symptoms in an 8-OH DPAT-induced rat PE model. Notably, compound 7 exhibited no risk of reducing sexual desire or impairing erectile function at therapeutic doses. Collectively, these findings identify N-aryl-N-acyl diamine as a promising scaffold for developing anti-PE therapeutics.