Rational Design and Synthesis of Highly Potent β‐Glucocerebrosidase Inhibitors

Abstract

Potenzielle niedermolekulare Wirkstoffe für die Behandlung der Gaucher‐Krankheit wurden synthetisiert. Die hoch wirksamen Inhibitoren der humanen β‐Glucocerebrosidase scheinen sowohl Kohlenhydrat‐ als auch hydrophobe Bindungsstellen zu erkennen. Der aktivste Inhibitor, 6‐Nonylisofagomin (siehe Schema), erreicht einen IC50‐Wert im subnanomolaren Bereich.

Molecular Basis for β‐Glucosidase Inhibition by Ring‐Modified Calystegine Analogues

“…[18] Compounds 8 and 9 were further evaluated as inhibitors of the recombinant human b-glucocerebrosidase (GCase; Imiglucerase, Cerezyme from Genzyme). The n-octyl derivative 9 (K i = 2.2 mm; IC 50 = 6.5 mm) was found to be a tenfold better inhibitor for this enzyme than the n-butyl derivative 8 (K i 24.8 mm; IC 50 value 64 mm), [19] which agrees with the correlation between lipophilicity (chain length) and the inhibitory activity that was observed in other glycomimetic families. [20] The kinetic determination of the inhibition constants for 8 and 9 with TmGH1, which was carried out at the pH optimum of catalytic activity for the enzyme (pH 5.8) afforded values of 1.1 and 0.28 mm, respectively (compared with 4 mm, 9 mm, 2 mm and 23 nm for 1-4, respectively).…”

Acceleration Effect of an Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope, Application, and Mechanistic Insights

“…(+)-Isofagomine is a potent selective b-glucosidase inhibitor that has recently received much attention in Gauchers disease therapy. [13] The enyne substrate 1 b, with an allylic hydroxy group, was synthesized by addition of propargylamine to butadiene monoxide, followed by protection of the imino group with a Boc group (71 % over two steps). The allylic hydroxy group-accelerated ring-closing enyne metathesis of 1 b efficiently provided cyclic product 2 b (> 99 %) in a short reaction time.…”

“…The residual CHCl 3 signal or tetramethylsilane were used as internal standards for 1 H and 13 C NMR in CDCl 3 . The C 6 D 6 itself was used as an internal standard for 13 C NMR in C 6 D 6 . The residual non-deuterated H 2 O signal was used as an internal standard for 1 H NMR, and acetonitrile was used as an internal standard in General procedure for allylic hydroxy group-accelerated ring-closing enyne metathesis: The first-generation Grubbs catalyst (4, 8, or 12 mol %) was added at room temperature under Ar to a CH 2 Cl 2 solution of an enyne substrate [24] containing an allylic hydroxy group.…”

Imaging of enzyme replacement therapy using PET

“…In order to demonstrate that GCase labeling was an active-site-dependent process, radioactive tagging was attempted in the presence of 6-nonylisofagomine, a potential active-site-specific chaperone known to be a potent inhibitor (IC 50 ¼ 0.6 nM) of the enzyme (see Fig. S5) (19). Indeed, incubation of GCase with β-DNP-[ 18 F]-FDG and 6-nonylisofagomine under identical conditions to those used previously resulted in no incorporation of radiolabel into the enzyme.…”