Synthesis of potent β-D-glucocerebrosidase inhibitors: N-alkyl-β-valienamines

Six homologous derivatives (N-butyl3a, hexyl 3b, octyl 3c, decyl 3d, tetradecyl 3e and stearyl 3f) of β-valienamine were synthesized. All have been shown to be potent and specific inhibitors of β-glucocerebrosidase, and to have no potency against glucosylceramide synthase (mouse liver microsomes). Among them, the N-octyl derivative possesses the strongest activity (IC50 3 × 10−8 M), being almost 10-fold more potent compared to the unsaturated 5a-carba-glucosylceramide 1. Compounds 3b and 3c are also moderate inhibitors of α-glucosidase (Bakerʹs yeast).