223771-83-3Relevant articles and documents
Microwave-assisted process for preparing N-nonyldeoxynojirimycin
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Paragraph 0038; 0049-0071, (2019/02/21)
The present invention relates to a method of manufacturing N-nonyl deoxynojirimycin having an excellent inhibitory activity against andalpha;-glucoside. To be specifically, the present invention relates to the method of manufacturing N-nonyl deoxynojirimycin using microwave which is manufactured by conducting a substitution reaction of deoxynojirimycin, which is a starting material, into 1-bromononane in the presence of K_2CO_3 base, diluting the same with a dimethyl formamide (DMF) solvent and conducting a heating reaction of the same by microwave.COPYRIGHT KIPO 2019
A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
supporting information, p. 14192 - 14197 (2017/10/17)
Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
Structure–Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2
Gu, Xingxian,Gupta, Vijayalaxmi,Yang, Yan,Zhu, Jin-Yi,Carlson, Erick J.,Kingsley, Carolyn,Tash, Joseph S.,Sch?nbrunn, Ernst,Hawkinson, Jon,Georg, Gunda I.
, p. 1977 - 1984 (2017/11/30)
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.
Pharmaceutically active piperidine derivatives
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, (2015/12/18)
Compounds of formula (I): wherein R represents various substituent groups, are useful as inhibitors of glucosylceramide synthase.
IMINOSUGARS AND METHODS OF TREATING ARENAVIRAL INFECTIONS
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Paragraph 0041; 0042, (2015/11/28)
Provided are methods of treating a disease or condition caused by or associated with a virus belonging to the Arenaviridae family using iminosugars, such as DNJ derivatives.
Identification of potent and selective glucosylceramide synthase inhibitors from a library of N-alkylated iminosugars
Ghisaidoobe, Amar,Bikker, Pieter,De Bruijn, Arjan C. J.,Godschalk, Frithjof D.,Rogaar, Eva,Guijt, Marieke C.,Hagens, Peter,Halma, Jerre M.,Van't Hart, Steven M.,Luitjens, Stijn B.,Van Rixel, Vincent H. S.,Wijzenbroek, Mark,Zweegers, Thor,Donker-Koopman, Wilma E.,Strijland, Anneke,Boot, Rolf,Van Der Marel, Gijs,Overkleeft, Herman S.,Aerts, Johannes M. F. G.,Van Den Berg, Richard J. B. H. N.
body text, p. 119 - 123 (2011/04/15)
Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.
METHODS OF TREATING POXVIRAL INFECTIONS
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Page/Page column 11, (2011/04/14)
Provided are methods of treating a disease or condition caused by or associated with a virus belonging to the Poxviridae family using iminosugars, such as DNJ derivatives.
IMINOSUGARS AND METHODS OF TREATING FILOVIRAL DISEASES
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Page/Page column 11, (2011/04/14)
Provided are methods of treating a disease or condition caused by or associated with a virus belonging to the Filoviridae family using iminosugars, such as DNJ derivatives.
METHODS OF TREATING ORTHOMYXOVIRAL INFECTIONS
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Page/Page column 11-12, (2011/04/14)
Provided are novel iminosugars and methods of treating and/or preventing a disease or condition caused by or associated with a virus belonging to the Orthomyxoviridae family using iminosugars, such as DNJ derivatives.
α-1-C-Octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease
Yu, Liang,Ikeda, Kyoko,Kato, Atsushi,Adachi, Isao,Godin, Guillaume,Compain, Philippe,Martin, Olivier,Asano, Naoki
, p. 7736 - 7744 (2007/10/03)
The most common lysosomal storage disorder, Gaucher disease, is caused by inefficient folding and trafficking of certain variants of lysosomal β-glucosidase (β-Glu, also known as β-glucocerebrosidase). Recently, Sawker et al. reported that the addition of subinhibitory concentrations (10 μM) of the pharmacological chaperone N-nonyl-1-deoxynojirimycin (NN-DNJ) (10) to Gaucher patient-derived cells leads to a 2-fold increase in activity of mutant (N370S) enzyme [Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15428]. However, we found that the addition of NN-DNJ at 10 μM lowered the lysosomal α-glucosidase (α-Glu) activity by 50% throughout the assay period in spite of the excellent chaperoning activity in N370S fibroblasts. Hence, we prepared a series of DNJ derivatives with an alkyl chain at the C-1α position and evaluated their in vitro inhibitory activity and potential as pharmacological chaperones for Gaucher cell lines. Among them, α-1-C-octyl-DNJ (CO-DNJ) (15) showed 460-fold stronger in vitro inhibitory activity than DNJ toward β-Glu, while NN-DNJ enhanced in vitro inhibitory activity by 360-fold. Treatment with CO-DNJ (20 μM) for 4 days maximally increased intracellular β-Glu activity by 1.7-fold in Gaucher N370 cell line (GM0037) and by 2.0-fold in another N370 cell line (GM00852). The addition of 20 μM CO-DNJ to the N370S (GM00372) culture medium for 10 days led to 1.9-fold increase in the β-Glu activity without affecting the intracellular α-Glu activity for 10 days. Only CO-DNJ showed a weak β-Glu chaperoning activity in the L444P type 2 variant, with 1.2-fold increase at 5-20 μM, and furthermore maximally increased the α-Glu activity by 1.3-fold at 20 μM. These experimental results suggest that CO-DNJ is a significant pharmacological chaperone for N370S Gaucher variants, minimizing the potential for undesirable side effects such as α-Glu inhibition.
