Synthesis and biological evaluation of four stereoisomers of PDMP-analogue, N-(2-decylamino-3-hydroxy-3-phenylprop- 1-yl)-β-valienamine, and related compounds

Article abstract of DOI:10.1016/S0960-894X(97)00341-7

All stereoisomers with regard to C-1 and 2 of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) analogue containing unsaturated (β-valienamine) and saturated 5a-carba-β-D-glucopyranosylamine (β-validamine) residues in place of morpholine moiety were synthesized. Although PDMP is a potent and specific glucosylceramide synthase inhibitor, the former valienamine analogues (4a-d) have been shown to be strong glucocerebrosidase inhibitors (IC₅₀ 3-7 x10^-7 M). The latter validamine analogues (5a-d) were also moderate glucocerebrosidase inhibitors (IC₅₀ 5-20 x 10^-6 M). A series of compounds synthesized lacked an inhibitory potency against the glucosyltransferase at all. Whereas the analogue 6a composed of epimeric α-valienamine residue did not possess any potency against both enzymes.