Tesofensine

Tesofensine (NS2330; CAS 195875-84-4; molecular formula C17H23Cl2N; molecular weight 312.28) is a triple monoamine reuptake inhibitor developed by NeuroSearch in the 1990s as a candidate for Alzheimer's disease and Parkinson's disease (where dopamine reuptake inhibition was hypothesized to provide motor symptom relief without the on-off fluctuations of L-DOPA). The compound failed to demonstrate efficacy in the original Alzheimer's and Parkinson's indications; weight loss observed as an adverse event in the central nervous system trials motivated repurposing for obesity, with Phase 2 data published in 2008 showing approximately 10 percent body weight reduction at 24 weeks at the 0.5 mg dose, substantially greater than the comparator orlistat and meaningfully greater than the GLP-1 agonist liraglutide at typical doses. Mechanism is competitive inhibition at the dopamine, norepinephrine, and serotonin transporters with similar affinity at all three sites; the integrated effect is monoamine elevation in mesolimbic, prefrontal, and hypothalamic targets that suppresses appetite and increases energy expenditure. The compound was advanced through Phase 3 by NeuroSearch and partner Saniona for obesity but Phase 3 enrollment was paused multiple times owing to safety signals (modest blood pressure elevation, dry mouth, insomnia, mood changes) and the program has progressed slowly relative to the more recent GLP-1 class. Saniona has continued development for hypothalamic obesity (Prader-Willi syndrome and acquired hypothalamic obesity from craniopharyngioma surgery), with the rationale that the central monoamine elevation may compensate for hypothalamic dysfunction in these niche populations. The compound is not approved in any jurisdiction. Plasma half-life is approximately 9 days, suitable for once-daily oral administration with steady-state achieved over 4 weeks.