| Autor: |
Ghisaidoobe AT; Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University , Einsteinweg 55, 2300 RA Leiden, The Netherlands., van den Berg RJ, Butt SS, Strijland A, Donker-Koopman WE, Scheij S, van den Nieuwendijk AM, Koomen GJ, van Loevezijn A, Leemhuis M, Wennekes T, van der Stelt M, van der Marel GA, van Boeckel CA, Aerts JM, Overkleeft HS |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2014 Nov 13; Vol. 57 (21), pp. 9096-104. Date of Electronic Publication: 2014 Oct 17. |
| DOI: |
10.1021/jm501181z |
| Abstrakt: |
This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of D-gluco and L-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (D-gluco and L-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted L-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their D-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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