Journal of Medicinal Chemistry p. 9096 - 9104 (2014)
Update date:2022-08-16
Topics:
Ghisaidoobe, Amar T.
Van Den Berg, Richard J. B. H. N.
Butt, Saleem S.
Strijland, Anneke
Donker-Koopman, Wilma E.
Scheij, Saskia
Van Den Nieuwendijk, Adrianus M. C. H.
Koomen, Gerrit-Jan
Van Loevezijn, Arnold
Leemhuis, Mark
Wennekes, Tom
Van Der Stelt, Mario
Van Der Marel, Gijsbert A.
Van Boeckel, Constant A. A.
Aerts, Johannes M. F. G.
Overkleeft, Herman S.
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.
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