Introduction：Basic information about Eliglustat hemitartrate CAS 928659-70-5, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Eliglustat hemitartrate Basic information
| Product Name: | Eliglustat hemitartrate |
| Synonyms: | Eliglustat (Tartrate);Eliglustat (hemitartrate);Eliglustat hemitartrate(Genz-99067);GENZ112638;(2R,3R)-2,3-Dihydroxysuccinic acid - N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide (1:2);GENZ-112638;GENZ 112638;GENZ112638;Eliglustat tartrate (Genz-112638);GENZ-99067;GENZ99067;GENZ 99067;GENZ-112638;GENZ112638;GENZ 112638;ELIGLUSTAT TARTRATE |
| CAS: | 928659-70-5 |
| MF: | C50H78N4O14 |
| MW: | 959.17272 |
| EINECS: | |
| Product Categories: | 1 |
| Mol File: | 928659-70-5.mol |
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Eliglustat hemitartrate Chemical Properties
| Melting point | >133°C (dec.) |
| storage temp. | -20°C Freezer, Under inert atmosphere |
| solubility | DMSO (Slightly), Methanol (Slightly) |
| form | Solid |
| color | White |
| InChIKey | KUBARPMUNHKBIQ-VTHUDJRQSA-N |
Safety Information
Eliglustat hemitartrate Usage And Synthesis
| Description | Eliglustat tartrate, developed and marketed by Genzyme Corporation(a subsidiary of Sanofi), was approved by the US FDA inAugust 2014 for the treatment of nonneuropathic (type 1) Gaucherdisease (GD1) in both treatment-naive and treatment-experiencedadult patients. It is the first oral treatment to be approved forfirst-line use in patients with Gaucher disease type 1, which is arare lysosomal storage disease characterized by accumulation of lipid glucosylceramide (GL-1) due to insufficient production of theenzyme glucosylceramidase. Clinical complications includehepatosplenomegaly, anemia, thrombocytopenia, and boneinvolvement. Eliglustat is a specific inhibitor of glucosylceramidesynthase with an IC50 of 10 ng/mL and acts as substratereduction therapy for GD1; it has demonstrated non-inferiorityto enzyme replacement therapy, which is the current standard ofcare, in Phase III trials. |
| Uses | Eliglustat Tartrate functions as an oral agent for treatment of Gaucher disease type 1, and lysosomal storage disorders in human. It also inhibits UDP-glucosylceramide synthase in mice thereby preventing Gaucher disease-associated with B-cell malignancy. |
| Definition | ChEBI: A tartrate that is the hemitartrate salt of eliglustat. A ceramide glucosyltransferase inhibitor used (as its tartrate salt) for treatment of Gaucher's disease. |
| Synthesis | Condensation of commercially availableS-(+)-2-phenyl glycinol (87) with phenyl bromoacetate (88)in acetonitrile in the presence of N,N-diisopropylethylamine(DIPEA) provided morpholin-2-one 89 upon treatment with HCl.Neutralization with NaHCO3 followed by coupling with aldehyde90 in refluxing EtOAc/toluene yielded oxazine adduct 91, whichwas isolated as a precipitate from methyl-tert-butyl ether (MTBE).The stereochemistry of the three new stereocenters in 91 can berationalized through the cycloaddition of an ylide intermediate inthe sterically-preferred S-configuration (generated by the reactionof the morpholinone 89 with aldehyde 90) with a second equivalentof the aldehyde. With the morpholinone in a chair conformationin which the phenyl group is equatorial, endo axial approachof the dipolarophile to the less-hindered face of the ylide and subsequentring flip of the morpholinone ring to a boat conformationpositions all exocyclic aryl substituents in a pseudoequatorial configuration. Opening of oxazine 91 with pyrrolidine in refluxingTHF followed by addition of HCl in refluxing MeOH gave amide92, which was reduced to amine 93 using LiAlH4 in refluxingTHF. Subsequent hydrogenation with Pd(OH)2 in EtOH cleavedthe phenylethanol group to give the free amine, which was convertedto dioxalate salt 94 by treatment with oxalic acid in methylisobutylketone (MIBK). Subjection of aminoethanol 94 to aqueoussodium hydroxide followed by coupling with palmitic acid Nhydroxysuccinimide(NHS)-ester (95) gave eliglustat as the correspondingfreebase (96) in 9.5% overall yield from 87. Salt formationwith L-tartaric acid (0.5 equiv) then provided eliglustat tartrate(XII). |
| in vitro | Eliglustat tartrate (Eliglustat hemitartrate) shows good potency with an IC50 of 24 nM and specificity against the target enzyme. Incubating K562 or B16/F10 cells for 72 h with increasing amounts of Genz-112638 (0.6-1000 nM) results in a dose-dependent reduction of both GM1 and GM3 cell surface levels. The mean IC50 value for inhibiting the cell surface presentation of GM1 in K562 cells was 24 nM (range 14-34 nM), and that for GM3 in B16/F10 cells was 29 nM (range 12-48 nM). |
| Drug interactions | Presently, no formal studies have been conducted to assess interactions between eliglustat tartrate and other drugs. Because eliglustat tartrate is metabolized by CYP2D6, potential toxicity might be observed in patients concurrently treated with known CYP2D6 inhibitors. Commonly used CYP2D6 inhibitors include, but are not limited to, albuterol, amiodarone, bupropion, chlorpheniramine, cimetidine, diphenhydramine, fluoxetine, haloperidol, hydroxyzine, metoclopramide, paroxetine, sertraline and thioridazine. Known inducers of CYP2D6 include phenobarbital, rifampin and dexamethasone[1]. |
| References | [1] Shayman, J A. “ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease.” Drugs of the future vol. 35,8 (2010): 613-620. |
Eliglustat hemitartrate Preparation Products And Raw materials
