Eliglustat | Glucosylceramide Synthase Inhibitor I Treatment for Gaucher Disease Type 1

Eliglustat [N-[(1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide] is a small-molecule, oral and potent inhibitor of the enzyme glucosylceramide synthase. This glucosylceramide analogue has been developed for the treatment of Gaucher disease type 1 in adults.

Inhibition of the enzyme glucosylceramide synthase reduces the accumulation of the lipid glucosylceramide in the liver, spleen, bone marrow and other organs [1, 2].

Eliglustat: 2D and 3D Structure

Eliglustat is the first oral treatment to be approved for first-line use in patients with Gaucher disease type 1. It received its first global approval in the US on 19 August 2014 for the treatment of Gaucher disease type 1 in treatment-naive and treatment-experienced adult patients.

Gaucher Disease Type 1 and Therapy

Gaucher disease (GD) type 1 is a rare autosomal recessive lysosomal storage disorder in which the lipid glucosylceramide accumulates in Gaucher cells in organs including the spleen, liver and bone marrow due to insufficient production of the enzyme glucosylceramidase. This leads to clinical manifestations that include enlargement of the spleen and liver, skeletal complications, anaemia and thrombocytopenia.

These cardinal features of GD have been shown to be responsive to enzyme replacement therapy (ERT) and substrate synthesis inhibition. Both therapeutic approaches enhance the clearance of the accumulated substrate glucosylceramide (GL1), by either restoring enzymatic\hydrolytic activity or reducing the concentration of substrate precursors to a level within the hydrolytic capacity of the mutant enzyme (glucocerebrosidase).

Substrate synthesis inhibition is alternatively referred to as substrate reduction therapy. This therapeutic option entails the inhibition of glucosylceramide synthase, a Golgi complex enzyme that catalyzes the formation of glucosylceramide from ceramide and uridine diphosphate glucose.

Two classes of orally administered glucosylceramide synthase inhibitors have been described; namely, iminosugars and analogs of d-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP). Miglustat [N-butyldeoxynojirimycin] an alkylated iminosugar, was the first oral substrate synthesis inhibitor to garner regulatory approval, based on clinical trials in adult patients with GD type 1, the non-neuropathic clinical variant. Eliglustat tartrate, a PDMP analog, is a first of its class to be launched [2].

Eliglustat Synthesis

WO2003008399A1: The patent details the synthetic procedures. Also lists procedures for various intermediates.

Identifications:

Experimental: ¹H NMR (CDCl₃) δ 7.15 (d, J= 8.5Hz, 2H), 6.70 (d, J= 8.5 Hz , 2H), 6.0 (d, J= 7.3, 1H), 4.96 (d, J= 3.8, 1H), 4.3-4.2 ( , 1H), 2.9-2.7 (m, 2H), 2.65-2.55 (m, 4H), 2.10 (t, J= 7.5, 2H), 1.75 (br s, 4H), 1.58- 1.46 ( , 2H), 1.32-1.16 (m, 24H), 0.9 (t, J= 6.7, 3H) ppm.

Sideeffects: The most common adverse events (AEs) reported by patients (greater than 20%) taking Eliglustat in clinical trials were fatigue, headache, nausea, diarrhoea, back pain, pain in the extremities and upper abdominal pain. Most adverse events occurred within the first 6 months of treatment and only 19 % of adverse events were considered to be related to the study drug.

Other adverse events reported included dizziness, asthenia, cough, dyspepsia, gastroesophageal reflux disease, constipation, palpitations and rash. A total of 3 %of patients discontinued treatment due to adverse events [1].

References:
1. Poole, R. M. Eliglustat: first global approval. Drugs 2014, 74(15), 1829-1836. (FMO only)
2. Pastores, G. M.; et. al. Eliglustat tartrate: an oral therapeutic option for Gaucher disease type 1. Clin Invest 2014, 4(1), 45-53. (FMO only)
3. Hirth, B. H.; et. al. Synthesis of udp-glucose: n-acylsphingosine glucosyltransferase inhibitors. WO2003008399A1