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

Xingxian Gu, Vijayalaxmi Gupta, Yan Yang, Jin Yi Zhu, Erick J. Carlson, Carolyn Kingsley, Joseph S. Tash, Ernst Schönbrunn, Jon Hawkinson, Gunda I. Georg

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4 Scopus citations

Abstract

Analogues of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal β-glucosidase 2 (GBA2) and the lysosomal β-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 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N-nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N-(1-(pentyloxy)methyl)adamantan-1-yl) derivative 35 f had Ki 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.

Original languageEnglish (US)
Pages (from-to)1977-1984
Number of pages8
JournalChemMedChem
Volume12
Issue number23
DOIs
StatePublished - Dec 7 2017

Bibliographical note

Funding Information:
This work was supported by the Contraception Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development through contracts HHSN275200503400C and HHSN275201300017C. We thank NICHD program officers Dr. H. K. Kim, Dr. Diana Blithe and Dr. Min Lee for their support of this program.

Keywords

  • N-butyl-1-deoxynojirimycin
  • aminocyclitols
  • enzyme inhibition
  • lysosomal glucosidase 1
  • non-lysosomal glucosidase 2

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