Identification and Development of Biphenyl Substituted Iminosugars as Improved Dual Glucosylceramide Synthase/Neutral Glucosylceramidase Inhibitors
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- 作者：Amar T. Ghisaidoobe ; Richard J. B. H. N. van den Berg ; Saleem S. Butt ; Anneke Strijland ; Wilma E. Donker-Koopman ; Saskia Scheij ; Adrianus M. C. H. van den Nieuwendijk ; Gerrit-Jan Koomen ; Arnold van Loevezijn ; Mark Leemhuis ; Tom Wennekes ; Mario van der Stelt ; Gijsbert A. van der Marel ; Constant A. A. van Boeckel ; Johannes M. F. G. Aerts ; Herman S. Overkleeft
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：November 13, 2014
- 年：2014
- 卷：57
- 期：21
- 页码：9096-9104
- 全文大小：573K
- ISSN：1520-4804
文摘
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.