Synthesis of the Key Intermediate, Diethyl 2-Acetylamino-2-(2-(4-octanoylphenyl)ethyl)propane-1,3-dioate, of the Immunomodulatory Agent FTY720 (Fingolimod)

Matsumoto, Namiko; Hirose, Ryoji; Sasaki, S.; Fujita, Tetsuro

doi:10.1248/cpb.56.595

Cited by 13 publications

(3 citation statements)

References 28 publications

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“…4,5) The structure of ISP-I was subsequently modified in order to reduce its toxicity, to improve its physicochemical properties and to identify the essential structure for immunosuppressive activity, and a candidate compound, FTY720, was obtained. 6) FTY720 was discovered by Tetsuro Fujita, of our group, in collaboration with Taito Co. and Yoshitomi Pharmaceutical Industries, Ltd. in Japan.…”

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Efficacy of Combination Treatment with Fingolimod (FTY720) Plus Pathogenic Autoantigen in a Glucose-6-phosphate Isomerase Peptide (GPI<sub>325–339</sub>)-Induced Arthritis Mouse Model

Yoshida

Tsuji

Watanabe

et al. 2013

Biological & Pharmaceutical Bulletin

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Fingolimod (FTY720) is known to have a significant therapeutic effect in various autoimmune disease models. Here, we examined FTY720 in a model of rheumatoid arthritis, induced by immunizing DBA/1 mice with a peptide consisting of residues 325 through 339 of glucose-6-phosphate isomerase (GPI325-339). The efficacy was evaluated in terms of macroscopic findings, inflammatory cell infiltration and autoantibody level. Prophylactic administration of FTY720 from the day of immunization significantly suppressed the development of paw swelling, but therapeutic administration of FTY720 from onset of symptoms on day 8-9 was less effective. Interestingly, however, combination treatment with FTY720 plus GPI325-339 for 5 d after onset of symptoms significantly reduced the severity of symptoms in all mice, and no relapse occurred after booster immunization. Taking into account the reported mechanism of action of FTY720, these results indicate that combination treatment with FTY720 plus pathogenic autoantigen might efficiently induce immune tolerance by sequestering circulating autoantigen-specific lymphocytes from blood and peripheral tissues to the secondary lymphoid tissues. Combination treatment with FTY720 plus pathogenic autoantigen may become a breakthrough treatment for remission-induction in patients with autoimmune diseases including rheumatoid arthritis.

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Efficacy of Combination Treatment with Fingolimod (FTY720) Plus Pathogenic Autoantigen in a Glucose-6-phosphate Isomerase Peptide (GPI<sub>325–339</sub>)-Induced Arthritis Mouse Model

Yoshida

Tsuji

Watanabe

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Several syntheses of 1 and of phosphate 3 have been accomplished . In contrast to phosphates such as 3 , phosphonate analogues are resistant to the action of lipid phosphate phosphatases and may offer improved cellular stability.…”

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Chiral Vinylphosphonate and Phosphonate Analogues of the Immunosuppressive Agent FTY720

Sun

Valentine

et al. 2009

J. Org. Chem.

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The first enantioselective synthesis of chiral isosteric phosphonate analogues of FTY720 is described. One of these analogues, FTY720-(E)-vinylphosphonate (S)-5, but not its R enantiomer, elicited a potent anti-apoptotic effect in intestinal epithelial cells, suggesting that it exerts its action via the enantioselective activation of a receptor. (S)-5 failed to activate the sphingosine 1-phosphate type 1 (S1P 1 ) receptor. FTY720 (2-amino-[2-(4-n-octylphenyl)ethyl]-1,3-propanediol, Fingolimod™, 1, Chart 1) is a synthetic analogue of the chiral sphingolipid myriocin (2). 1 As an analogue of sphingosine, FTY720 is phosphorylated in vivo by sphingosine kinases, affording (S)-FTY720-phosphate (3), which activates four of the five known sphingosine 1-phosphate (S1P, 2a) G proteincoupled receptors. 2 Internalization and subsequent polyubiquitination of the S1P receptors leads to their proteasomal degradation and renders the cells unresponsive to S1P; therefore, lymphocytes are not capable of recirculation to peripheral inflammatory tissues. 3 Thus, FTY720 has therapeutic potential, and in fact is the first S1P receptor modulator that has entered the stage of a phase-III clinical study. 4 Several syntheses of 1 5 and of phosphate 3 have been accomplished. 6 In contrast to phosphates such as 3, phosphonate analogues are resistant to the action of lipid phosphate phosphatases and may offer improved cellular stability. A racemic mixture of the nonhydrolyzable phosphonate analogue of FTY720 (4) was reported in which the C-O-P bond is replaced with robert.bittman@qc.cuny.edu). Supporting Information Available: Experimental details for the synthesis of compounds 6-8, 10, 11, 12, 16, and 4, and NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org/ NIH Public Access a C-C-P bond; 2b rac-4 was found to be a high-affinity agonist of the S1P-type 1 receptor (S1P 1 ), with a similar potency as (S)-3. 7 We report here the first asymmetric syntheses of the chiral phosphonate analogues of FTY720, (R)-4 and (S)-4. Oxazoline intermediate (S)-14 (Scheme 1), prepared by a modification of our previous route, 6c was further elaborated to give the corresponding (E)-vinylphosphonate analogue (S)-5. We have included a preliminary pharmacological characterization of the effects of these analogues on the non-transformed rat intestinal epithelial cell line IEC-6. This study revealed that (S)-5, but not its (R) enantiomer, exerts a potent anti-apoptotic effect in a camptothecin (CPT)-induced apoptosis model. 8 Unlike phosphate (S)-3, (S)-5 did not activate the S1P 1 receptor of the Endothelial Differentiation Gene (EDG) family of G protein-coupled receptors, making it a novel enantioselective probe activating a cytoprotective mechanism against apoptosis induced by DNA damage.Wittig reaction of 4-bromobenzaldehyde with the ylide of n-heptyltriphenylphosphonium bromide gave arylalkene 6 as an E,Z (1:3) mixture (Scheme 1). Sonogashira coupling between 6 and 4-(phenylmethoxy...

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“…Different synthetic pathways could be used to manufacture fingolimod, which may add other potential process‐related impurities depending on the manufacturing process, starting materials and intermediates used (Adachi et al, 1995; Kiuchi et al, 2000; Durand et al, 2000; Kalita et al, 2001; Seidel et al, 2004; Sugiyama et al, 2005; Kim et al, 2006; Matsumoto et al, 2008; Calzavara & McNulty, 2011; Feng et al, 2012; Kandagatla et al, 2013; Shaikh et al, 2015; Yan et al, 2015; Balaev et al, 2017; Maruthi Raju et al, 2017a, 2017b; Lin et al, 2018; Vinigari et al, 2019). To the prove the absence of additional impurities and ensure drug substance quality according to International Conference on Harmonization (ICH) guideline Q3A, potential process‐related impurities should be evaluated and pharmacopoeia methods should be validated by the addition of these impurities, or in‐house methods should be developed and validated including all pharmacopoeia and in‐house impurities.…”

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Synthesis, characterization and control of eight process‐related and two genotoxic fingolimod impurities by a validated RP‐UPLC method

Atici¹,

Yazar²,

Rıdvanoğlu³

2022

Biomedical Chromatography

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An HPLC method has been described in the European Pharmacopoeia and United States Pharmacopeia for the determination of nine organic impurities (imp A-I) in fingolimod hydrochloride, a synthetic sphingosine-1-phosphate receptor modulator. The manufacturing process of fingolimod hydrochloride consists of multistep chemical synthesis wherein controls of precursors, intermediates and process steps should be performed to assure the final quality of the drug substance. We synthesized and isolated eight process-related impurities (FINI imp A-H) of fingolimod, which were different from the pharmacopoeial impurities. One unknown processrelated impurity was found as a key intermediate (FINI) and was identified by LC-MS. Characterization of all of the impurities were done using spectroscopic techniques ( 1 H and 13 C NMR, FTIR, MS), and the mechanistic pathways to the formation of these impurities were also discussed. Two of these impurities were evaluated as potential genotoxic impurities owing to their alerting structures and alkylating properties (alkyl sulfonates and alkyl halides, class 3, ICH M7). We also developed and validated an RP-UPLC method in line with ICH Q2 guidelines for control these impurities (FINI imp A-H) and to assure the pharmacopoeial quality drug substance.

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Synthesis of the Key Intermediate, Diethyl 2-Acetylamino-2-(2-(4-octanoylphenyl)ethyl)propane-1,3-dioate, of the Immunomodulatory Agent FTY720 (Fingolimod)

Abstract: The key intermediate, diethyl 2-acetylamino-2-(2-(4-octanoylphenyl)ethyl)propane-1,3-dioate (13), for the immunomodulatory agent FTY720 (2: fingolimod) was synthesized via Michael addition of diethyl(acetylamino)malonate (6) to 4-octanoylstyrene (12).

Cited by 13 publications

References 28 publications

Efficacy of Combination Treatment with Fingolimod (FTY720) Plus Pathogenic Autoantigen in a Glucose-6-phosphate Isomerase Peptide (GPI<sub>325–339</sub>)-Induced Arthritis Mouse Model

Efficacy of Combination Treatment with Fingolimod (FTY720) Plus Pathogenic Autoantigen in a Glucose-6-phosphate Isomerase Peptide (GPI<sub>325–339</sub>)-Induced Arthritis Mouse Model

Chiral Vinylphosphonate and Phosphonate Analogues of the Immunosuppressive Agent FTY720

Synthesis, characterization and control of eight process‐related and two genotoxic fingolimod impurities by a validated RP‐UPLC method

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