title: Identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase/neutral glucosylceramidase inhibitors.
abstract: 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.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University , Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Amar T
authors.initials: AT
authors.lastname: Ghisaidoobe
authors.forename: Richard J B H N
authors.initials: RJ
authors.lastname: van den Berg
authors.forename: Saleem S
authors.initials: SS
authors.lastname: Butt
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Donker-Koopman
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.forename: Adrianus M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Koomen
authors.forename: Arnold
authors.initials: A
authors.lastname: van Loevezijn
authors.forename: Mark
authors.initials: M
authors.lastname: Leemhuis
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Constant A A
authors.initials: CA
authors.lastname: van Boeckel
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis* / Q000494:pharmacology; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D017485:1-Deoxynojirimycin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D001617:beta-Glucosidase; C517537:GBA2 protein, human; D005962:Glucosylceramidase