TCH-346, an anti-apoptotic compound, is under development by Novartis for the potential treatment of
Parkinson's disease (PD) and
motor neuron disease [271447,342937]. By September 1999, phase I clinical trials for PD were underway [342937]. The compound was discovered in a screen for molecules with both
norepinephrine uptake and
MAO inhibiting properties but, although it had anti-apoptotic properties, it did not inhibit MAOA or
MAO-B [333136,332004]. The compound increases lifespan in the progressive motorneuropathy mouse model and prevents
ischemia in models of
ischemia and seizure [288893]. In vivo, it shows neurorescuing and anti-apoptotic properties in PC12 cells and cerebellar granule cells, among others, at concentrations of 0.1 pM to 10 microM, suggesting that its action might prove potentially useful against Alzheimer's and/or
Parkinson's disease [332004]. The compound has also shown neurorescuing properties in rat pups after
axotomy, rat hippocampal CA1 neurons after transient
ischemia/
hypoxia and mouse nigral dopaminergic (DA) neurons
after treatment with
MPTP in doses ranging between 0.0003 and 0.1 mg/kg po or sc, depending on the model [333136]. Data presented by the University of Nijmengen and the Free University of Amsterdam show that
TCH-346 improves the behavioral and enzymatic outcome in the rat 6-OH-dopamine model of
Parkinson's disease.
TCH-346 (0.0014 mg/kg sc bid) prevented abnormal stepping (open field test) and prevented increases in fore and hind-paw retraction time.
TCH-346 also improved acquisition in the Morris water maze task and, at doses between 0.0014 and 0.14 mg/kg, prevented reduction in
tyrosine hydroxylase immunoreactivity [345259]. Affinity binding studies with
TCH-346 showed that GAPDH is the target [294902,283200]. Differential display RT-PCR also showed that
protein-isoaspartyl-methyl
transferase is induced by the
drug [283200].