Structure-Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2.

ABSTRACT: Analogues of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal ?-glucosidase?2 (GBA2) and the lysosomal ?-glucosidase?1 (GBA1). Compounds 5?a-6?f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB-DGJ (N-butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N-(n-butyl)- and N-(n-nonyl)-DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N-(n-butyl)- (35?a), N-(n-nonyl)-4-amino-5-(hydroxymethyl)cyclopentane- (35?b), and N-(1-(pentyloxy)methyl)adamantan-1-yl)-1,2,3-triol (35?f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1?mm), with the exception of 35?f, which inhibited CGT with an IC₅₀ value of 1?mm. The N-butyl analogue 35?a was 100-fold selective for inhibiting GBA1 over GBA2 (K_i values of 32?nm and 3.3??m for GBA1 and GBA2, respectively). The N-nonyl analogue 35?b displayed a K_i value of ?14?nm for GBA1 inhibition and a K_i of 43?nm for GBA2. The N-(1-(pentyloxy)methyl)adamantan-1-yl) derivative 35?f had K_i values of ?16 and 14?nm for GBA1 and GBA2, respectively. The related N-bis-substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono-substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.

SUBMITTER: Gu X 

PROVIDER: S-EPMC5725710 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature