AMP-deoxynojirimycin (AMP-DNM) is an orally available iminosugar that acts as a reversible, potent and selective inhibitor against the non-lysosomal glucosylceramidase GBA2 (IC50 = 1.7 nM) over the glucosylceramide synthase (GCS, UGCG), ER alpha-glucosidases, the lysosomal glucocerebrosidase GBA (IC50 = 0.16 μM) and alpha-glucosidase GAA (IC50 = 0.87 μM). AMP-DNM selectively inhibits cellular GBA2 in cultures (GBA2/GBA IC50 = 0.3 nM/100 nM; human melanoma cells) and exhibits in vivo therapeutic efficacy in murine models of obesity (100 mg/kg/day p.o.) and colitis (10-50 mg/kg/day via i.p. or 1.25-6.25g/kg chow).
Orally available, potent, selective non-lysosomal glucosylceramidase GBA2 inhibitor with therapeutic efficacy in murine models of obesity and colitis in vivo.
Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations
The Journal of Biological Chemistry, 294(11), 3853-3871 (2019)
Cytosolic glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease
Neurobiology of Disease, 127, 242-252 (2019)
Reduction of glycosphingolipid biosynthesis stimulates biliary lipid secretion in mice
Hepatology, 49(2), 637-645 (2009)
Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin protects against the inflammatory response in hapten-induced colitis
International Immunopharmacology, 4(7), 939-951 (2004)
Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation
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