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Anidulafungin Molecular Structure 2.png

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Anidulafungin

V-Echinocandin

CAS Number 166663-25-8

N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide

  • LY-307853
  • LY-329960
  • LY-333006
  • LY303366
  • VEC
  • VER-002

1H NMR (700 MHz, d6-DMSO) δ 0.91 (t, 3H), 1.12 (d, 3H), 1.36 (m, 2H), 1.41 (m, 2H), 1.74 (p, 2H), 1.88 and 1.97 (overlapped, 2H), 3.85 (overlapped, 1H), 4.01 (t, 2H), 4.35 (overlapped, 1H), 4.44 (m, 1H), 4.76 (m, 1H), 4.80 (m, 1H), 5.02 (m, 1H), 5.07 (d, 1H), 5.52 (d, 1H), 7.04 (d, 1H), 7.66 (d, 1H), 7.74 (d, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.14 (broad s, 1H), 8.60 (d, 1H). IR (cm−1)

KBr νmax; 3450 (O−H), 2932 (C−H), 2871 (C−H), 1632 (C═O), 1517 (Ar), 1488 (Ar), 1248 (C−O), 821 (C−H out-of-plane bending Ar 2 adj H’s).

Anidulafungin (brand names: Eraxis (in U.S. and Russia), Ecalta (in Europe)) is a semisynthetic echinocandin used as anantifungal drug. Anidulafungin was originally manufactured and submitted for FDA approval by Vicuron Pharmaceuticals.[1] Pfizeracquired the drug upon its acquisition of Vicuron in the fall of 2005.[2] Pfizer gained approval by the Food and Drug Administration(FDA) on February 21, 2006;[3] it was previously known as LY303366. Preliminary evidence indicates it has a similar safety profile tocaspofungin. Anidulafungin has proven efficacy against esophageal candidiasis, but its main use will probably be in invasive Candidainfection;[4][5][6] it may also have application in treating invasive Aspergillus infection. It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (1→3)-β-D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall.

Pharmacodynamics and pharmacokinetics

Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.[7]

Distribution: 30–50 L. Protein binding: 84%.

Anidulafungin is not evidently metabolized by the liver. This specific drug undergoes slow chemical hydrolysis to an open-ring peptide which lacks antifungal activity. The half-life of the drug is 27 hours. Thirty percent is excreted in the feces (10% as unchanged drug). Less than 1% is excreted in the urine.[8][9][10]

Mechanism of action

Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1→3)-β-D-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity.[11]

Semisynthesis

Anidulafungin is manufactured via semisynthesis. The starting material is echinocandin B (a lipopeptide fermentation product ofAspergillus nidulans or the closely related species, A. rugulosus), which undergoes deacylation (cleavage of the linoleoyl side chain) by the action of a deacylase enzyme from the bacterium Actinoplanes utahensis;[12] in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin[11][13] is synthesized.

Aspergillus nidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.

ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-dihydroxy-N -[[4“-(pentyloxy)[1,1′:4′,1”-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients:

50 mg/vialfructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

100 mg/vial – fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

The empirical formula of anidulafungin is C58H73N7O17 and the formula weight is 1140.3. The structural formula is

ERAXIS™ (anidulafung in) Structural Formula Illustration

Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% DextroseInjection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).

SYNTHESIS

J MED CHEM 1995, 38 3271-3281

Semisynthetic Chemical Modification of the Antifungal Lipopeptide …

pubs.acs.org/doi/abs/10.1021/jm00017a012

by M Debono – ‎1995 – ‎Cited by 113 – ‎Related articles

Aug 1, 1995 – J. Med. Chem. , 1995, 38 (17), pp 3271–3281. DOI: 10.1021/jm00017a012 … Journal ofMedicinal Chemistry 2001 44 (16), 2671-2674

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide “nucleus” as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.

str1

PATENT

US 5965525

http://www.google.co.in/patents/US5965525

PATENT

US 4293482

http://www.google.co.in/patents/US4293482

Paper

Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/d-Fructose (Eraxis)

Chemical Research and Development, Pfizer Inc. Global Research and Development Laboratories, Eastern Point Road, Groton, Connecticut 06340, U.S.A.
Org. Process Res. Dev., 2008, 12 (3), pp 447–455
DOI: 10.1021/op800055h

http://pubs.acs.org/doi/abs/10.1021/op800055h

* Corresponding author. E-mail: timothy.norris@pfizer.com. Telephone: +860 441 4406 . Fax: +860 686 5340.

Abstract Image

Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and d-fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN·HCl) and the active ester 1-({[4′′-(pentyloxy)-1,1′:4′,1′′-terphenyl-4-yl]carbonyl}oxy)-1H-1,2,3-benzotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.

str1

References

  1.  PRNewswire. Vicuron Pharmaceuticals Files New Drug Application (NDA) for Anidulafungin for Treatment of Invasive Candidiasis/Candidemia 08-18-2005.
  2. Jump up^ PRNewswire. Vicuron Pharmaceuticals Stockholders Approve Merger With Pfizer 08-15-2005
  3.  “FDA Approves New Treatment for Fungal Infections”. FDA News Release. Food and Drug Administration. 2006-02-21. Archived from the original on 10 July 2009. Retrieved 2009-08-01.
  4.  Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T (2004). “Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia”. Antimicrob Agents Chemother 48 (6): 2021–4.doi:10.1128/AAC.48.6.2021-2024.2004. PMC 415613. PMID 15155194.
  5. Jump up^ Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ (2005). “In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole”. J Clin Microbiol 43 (11): 5425–7.doi:10.1128/JCM.43.11.5425-5427.2005. PMC 1287823. PMID 16272464.
  6. J Pfaller MA, Diekema DJ, Boyken L, Messer SA, Tendolkar S, Hollis RJ, Goldstein BP (2005). “Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis”. Antimicrob Agents Chemother 49 (11): 4795–7. doi:10.1128/AAC.49.11.4795-4797.2005.PMC 1280139. PMID 16251335.
  7. Jump up^ “Eraxis at RxList”. 2009-06-24. Retrieved 2009-08-01.
  8.  Trissel LA and Ogundele AB, “Compatibility of Anidulafungin With Other Drugs During Simulated Y-Site Administration,”Am J Health-Sys Pharm, 2005, 62:834-7.
  9.  Vazquez JA, “Anidulafungin: A New Echinocandin With a Novel Profile,” Clin Ther, 2005, 27(6):657-73.
  10. Jump up^ Walsh TJ, Anaissie EJ, Denning DW, et al., “Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America,” Clin Infect Dis, 2008, 46(3):327-60
  11. Denning DW (1997). “Echinocandins and pneumocandins – a new antifungal class with a novel mode of action”. J Antimicrob Chemother 40 (5): 611–614. doi:10.1093/jac/dkf045.PMID 9421307.
  12.  Lei Shao; Jian Li; Aijuan Liu; Qing Chang; Huimin Lin; Daijie Chen (2013). “Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains”. Applied and Environmental Microbiology 79 (4): 1126–1133. doi:10.1128/AEM.02792-12. PMC 3568618. PMID 23220968.
  13.  “Anidulafungin EMA Europa” (PDF).
Anidulafungin
Anidulafungin Molecular Structure 2.png
Systematic (IUPAC) name
N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide
Clinical data
Trade names Eraxis
AHFS/Drugs.com Monograph
Pharmacokinetic data
Protein binding 84 %
Biological half-life 40–50 hours
Identifiers
CAS Number 166663-25-8 Yes
ATC code J02AX06 (WHO)
PubChem CID 166548
DrugBank DB00362 Yes
ChemSpider 21106258 Yes
UNII 9HLM53094I Yes
KEGG D03211 
ChEBI CHEBI:55346
ChEMBL CHEMBL1630215 
Chemical data
Formula C58H73N7O17
Molar mass 1140.24 g/mol

//////////FUNGIN, ANIDULAFUNGIN, Eraxis , Ecalta,  semisynthetic echinocandin, anantifungal drug, FDA 2006, PFIZER, LY-307853, LY-329960, LY-333006, LY303366, VEC, VER-002, 166663-25-8, Eli Lilly and Company Inc.

STR1

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]6C[C@@H](O)[C@@H](O)NC(=O)C4[C@@H](O)[C@@H](C)CN4C(=O)C(NC(=O)C(NC(=O)C5C[C@@H](O)CN5C(=O)C(NC6=O)[C@@H](C)O)[C@@H](O)[C@H](O)c7ccc(O)cc7)[C@@H](C)O

Supporting Info


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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