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Showing posts with label VINTAFOLIDE. Show all posts
Showing posts with label VINTAFOLIDE. Show all posts

Friday 28 August 2015

VINTAFOLIDE



Vintafolide, EC-145  , MK-8109
mw 1917.041, cas 742092-03-1, mf C86 H109 N21 O26 S2
(2S)-2-[(4-{[(2-amino-4-oxo-3H-pteridin-6-yl)methyl]amino}phenyl)formamido]-4-{[(1S)-1-{[(1S)-4-carbamimidamido-1-{[(1S)-2-carboxy-1-{[(1S)-2-carboxy-1-{[(1R)-1-carboxy-2-({2-[({[(1R,9R,10S,11R,12R,19R)-12-ethyl-4-[(13S,15R,17S)-17-ethyl-17-hydroxy-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-10,11-dihydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraen-10-yl]formohydrazido}carbonyl)oxy]ethyl}disulfanyl)ethyl]carbamoyl}ethyl]carbamoyl}ethyl]carbamoyl}butyl]carbamoyl}-2-carboxyethyl]carbamoyl}butanoic acid
Vincaleukoblastin-23-oic acid, O4-deacetyl-, 2-[(2-mercaptoethoxy)carbonyl]hydrazide, disulfide with N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-γ-glutamyl-L-α-aspartyl-L-arginyl-L-α-aspartyl-L-α-aspartyl-L-cysteine
Endocyte innovator
Vintafolide is an investigational targeted cancer therapeutic currently under development by Endocyte and Merck & Co.[1] It is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is overexpressed on certain cancers, such as ovarian cancer, and a potent chemotherapy drug, vinblastine.[2] It is being developed with a companion imaging agent, etarfolatide, that identifies patients that express the folate receptor and thus would likely respond to the treatment with vintafolide.[3] A Phase 3 study evaluating vintafolide for the treatment of platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study(TARGET trial) in non-small-cell lung carcinoma (NSCLC) are ongoing.[4] Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.[5]
A Marketing Authorization Application (MAA) filing for vintafolide and etarfolatide for the treatment of patients withfolate receptor-positive platinum-resistant ovarian cancer in combination with doxorubicin, pegylated liposomal doxorubicin (PLD), has been accepted by the European Medicines Agency.[6] The drug received an orphan drug status in Europe in March 2012.[1] Merck & Co. acquired the development and marketing rights to this experimental cancer drug from Endocyte in April 2012.[1] The drug received orphan drug status in Europe in March 2012.[3]Endocyte remains responsible for the development and commercialization of etarfolatide, a non-invasive companion imaging agent used to identify patients expressing the folate receptor that will likely respond to treatment with vintafolide.[4] Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.[5]
In 2014 Merck and Endocyte stopped a late-stage study of vintafolide in treating ovarian cancer on the recommendation of a data safety monitoring board, saying that the drug failed to improve progression-free survival.[7]
Vintafolide is folate-conjugated with DAVBLH, which is a derivative of the vinca alkaloid vinblastine.Vinblastine is a microtubule-destabilizing agent that binds tubulin and causes M phase-specific cell cycle arrest and apoptosis of mitotically active cells. Vinblastine is an extremely potent chemotherapeutic agent but has significant toxicities including bone marrow suppression, neurotoxicity, gastrointestinal toxicity and vesicant injury.
Endocyte’s desacetylvinblastinehydrazide/folate conjugate (EC-145) is a folate-targeted cytotoxic anticancer drug in early development for the treatment of non-small cell lung cancer (NSCLC) and breast cancer. The compound had been pre-registered in the E.U. by Merck for the treatment of ovarian cancer, but the application was withdrawn due to lack of efficacy.
In 2012, the product was licensed to Merck & Co. by Endocyte for worldwide exclusive development and commercialization. In 2014, however, this license agreement was terminated and Endocyte regained all rights.
Folates can serve as one-carbon donors in reactions that are critical in the de novo biosynthesis of purines and thymidylate, amino acid metabolism and methylation reactions. Folate can enter a cell by two routes: RFC or by membrane-bound FRs. RFC is a bidirectional anion transporter that is the normal entry method for reduced folates in most cells. By contrast, FRs are expressed in a limited distribution in normal tissues but are overexpressed in multiple cancers including ovarian, lung, breast and colorectal cancer. FRs bind folate derivatives with high affinity and mediate their internalization by endocytosis. Given that FRs are not typically expressed on the luminal surface of epithelial cells, making them inaccessible to normal circulation, they are attractive therapeutic targets with limited toxicity. In addition to the therapeutic agent vintafolide, a radiodiagnostic agent (99mTc-etarfolatide [EC20]) has been developed to allow single-photon emission computed tomography (SPECT) imaging to identify FR-expressing tissues (tumors).
In 2012, orphan drug designations were assigned in the E.U. for the treatment of ovarian cancer and to be used with folic acid for the diagnosis of positive folate-receptor status in ovarian cancer. In 2013, orphan drug designation was assigned in the U.S. for the treatment of ovarian cancer.
Vintafolide is a water-soluble derivative of folic acid and the vinca alkaloid DAVLBH. The molecules are connected through a hydrophilic L-peptide spacer and a disulfide linker (Figure 1). The disulfide linker serves as a cleavable bond that is necessary for drug release following receptor mediated endocytosis. The disulfide bond is reduced in the acidic environment of the endosome, leading to efficient release of vinblastine.

Vintafolide.
DAVBLH: Desacetylvinblastine hydrazide




Structure of vintafolide and mechanism of release of the payload in the endosome.

Mechanism of action

Folate is required for cell division, and rapidly dividing cancer cells often express folate receptors in order to capture enough folate to support rapid cell growth. Elevated expression of the folate receptor occurs in many diseases, including other aggressively growing cancers and inflammatory disorders.[8] Vintafolide binds to the folate receptor and is subsequently taken up by the cell through a natural internalization process called endocytosis. Once inside the cell, vintafolide’s linker releases the chemotherapy drug which kills the cell.[3]
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Bioorganic & Medicinal Chemistry Letters (2006), 16(19), 5093-5096
http://www.sciencedirect.com/science/article/pii/S0960894X06008079
An efficient synthesis of the folate receptor (FR) targeting conjugate EC145 is described. EC145 is a water soluble derivative of the vitamin folic acid and the potent cytotoxic agent, desacetylvinblastine monohydrazide. Both molecules are connected in regioselective manner via a hydrophilic peptide spacer and a reductively labile disulfide linker.


………approach for the design and regioselective synthesis of a FA-vinca alkaloid conjugate 1 (EC145,BELOW). As indicated in the retrosynthetic scheme, 1 can be assembled by tethering a FA-Spacer unit 2 to the highly potent cytotoxic molecule, desacetylvinblastine monohydrazide 3, via a linker containing a reducible disulfide bond. The latter is important for drug delivery applications since real-time imaging using a fluorescence resonance energy transfer technique has recently demonstrated that reduction-mediated release of the drug cargo from a disulfide linked FA-conjugate efficiently occurs within the endosomes of cancer cells.
Reagents and conditions: (i) a—Fmoc-Asp(OtBu)-OH, PyBOP, DIPEA, RT, 1h; b—20% ...
Scheme 1.
Reagents and conditions: (i) a—Fmoc-Asp(OtBu)-OH, PyBOP, DIPEA, RT, 1 h; b—20% piperidine/DMF, rt, 10 min; (ii) a—Fmoc-Arg(Pbf)-OH, PyBOP, DIPEA, rt, 1 h; b—20% piperidine/DMF, rt, 10 min; (iii) a—Fmoc-Glu-OtBu, PyBOP, DIPEA, rt, 1 h; b—20% piperidine/DMF, rt, 10 min; (iv) N10-TFA-pteroic acid, PyBOP, DIPEA, rt, 1.5 h; (v) TFA/H2O/TIPS/EDT (92.5:2.5:2.5:2.5), rt, 1 h; (vi) aq NH4OH, pH 9.3, rt, 1 h.

Selected 1H NMR data for 2 (D2O, 300 MHz): δ 8.68 (s, 1H, FA H-7), 7.57 (d, 2H,J = 8.4 Hz, FA H-12 & 16), 6.67 (d, 2H, J = 9 Hz, FA H-13 & 15), 4.40–4.75 (series of m, 5H), 4.35 (m, 2H), 4.16 (m, 1H), 3.02 (m, 2H), 2.55–2.95 (series of m, 8H), 2.42 (m, 2H), 2.00–2.30 (m, 2H), 1.55–1.90 (m, 2H), 1.48 (m, 2H).

1H NMR for compound 6 (DMSO-d6, 300 MHz): δ 8.38 (m, 1H), 8.16 (dt, 1H, J = 8 Hz, 1 Hz), 8.02 (dt, 1H, J = 8 Hz, 1 Hz), 7.88 (ddd, 1H, J = 8 Hz, 7 Hz, 1 Hz), 7.7 (m, 2H), 7.63 (ddd, 1H, J = 8 Hz, 7 Hz, 1 Hz,), 7.4–7.2 (br, 1H), 7.2 (m, 1H), 4.72 (t, 2H,J = 6 Hz), 3.36 (t, 2H, J = 6 Hz).

Selected 1H NMR data for EC145 (D2O, 300 MHz): δ 8.67 (s, 1H, FA H-7), 7.50 (br s, 1H, VLB H-11′), 7.30–7.40 (br s, 1H, VLB H-14′), 7.35 (d, 2H, J = 7.8 Hz, FA H-12 & 16), 7.25 (m, 1H, VLB H-13′), 7.05 (br s, 1H, VLB H-12′), 6.51 (d, 2H, J = 8.7 Hz, FA H-13 & 15), 6.4 (s, 2H, VLB H-14 & 17), 5.65 (m, 1H, VLB H-7), 5.5 (m, 1H, VLB H-6), 4.15 (m,1H, VLB H-8′), 3.82 (s, 3H, VLB C18 –CO2CH3), 3.69 (s, 3H, VLB C16 –OCH3), 2.8 (s, 3H, VLB N–CH3), 1.35 (br s, 1H, VLB H-3′), 1.15 (m, 1H, VLB H-2′), 0.9 (t, 3H, J = 7 Hz, VLB H-21′), 0.55 (t, 3H, J = 6.9 Hz, VLB H-21).
VINCLICK ON IMAGE FOR CLEAR VIEW
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WO 2004069159
http://www.google.com/patents/WO2004069159A2?cl=en
EXAMPLE 16b
Figure imgf000076_0003
The compounds of Examples 16a and 16b were prepared from the peptidyl fragment Pte-Glu-Asp-Arg-Asp-Asp-Cys-OH , prepared according to the general procedure described in Scheme 12. The Michael addition of this peptidyl fragment to the maleimido derivative of seco-CBI-bis-indole resulted in the folate conjugates Example 16a. The peptidyl fragment also reacted with either the thiosulfonate or pyridyldithio-activated vinblastine to form Example 16b. The maleimido derivative of seco-CBI-bis-indole, and the thiosulfonate and pyridyldithio- activated vinblastine intermediates were prepared using the procedures described herein for other examples.

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https://www.google.com/patents/WO2012142281A1?cl=en
Folate-targeted drugs have been developed and are being tested in clinical trials as cancer therapeutics. EC145, also known as vintafolide, comprises a highly potent vinca alkaloid cytotoxic compound, desacetylvinblastine hydrazide (DAVLBH), conjugated to folate. The EC 145 molecule targets the folate receptor found at high levels on the surface of epithelial tumors, including non-small cell lung carcinomas (NSCLC), ovarian, endometrial and renal cancers, and others, including fallopian tube and primary peritoneal carcinomas. It is believed that EC 145 binds to tumors that express the folate receptor delivering the vinca moiety directly to cancer cells while avoiding normal tissue. Thus, upon binding, EC 145 enters the cancer cell via endocytosis, releases DAVLBH and causes cell death or inhibits cell function. EC 145 has the following formula
Figure imgf000002_0001
EC145
and has been accorded the Chemical Abstracts Registry Number 742092-03-1. As used herein, according to the context, the term EC 145 means the compound, or a pharmaceutically acceptable salt thereof; and the compound may be present in a solid, solution or suspension in an ionized form, including a protonated form. EC145 is disclosed in U.S. Patent No. 7,601,332; and particular uses and an aqueous liquid pH 7.4, phosphate-buffered formulation for intravenous administration are disclosed in WO 2011/014821. As described in WO 2011/014821, it is necessary to store the aqueous liquid formulation in the frozen state to ensure its stability. To avoid this necessity, a formulation is needed which has adequate stability at ambient temperature.
As one aspect of the invention described herein, there is provided a pharmaceutical composition of EC145 which is a lyophilized solid which has adequate stability for storage at ambient temperature and which is capable of redissolving in an aqueous diluent prior to administration.
In another aspect of the invention, there is provided a pharmaceutical composition of EC 145 which is an X-ray amorphous solid which has adequate stability for storage at ambient temperature and which is capable of redissolving in an aqueous diluent prior to administration.
Systematic (IUPAC) name
N-(4-{[(2-Amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-γ-glutamyl-L-α-aspartyl-L-arginyl-L-α-aspartyl-L-α-aspartyl-L-cysteine disulfide with methyl (5S,7R,9S)-5-ethyl-9-[(3aR,4R,5S,5aR,10bR,13aR)-3a-ethyl-4,5-dihydroxy-8-methoxy-6-methyl-5-({2-[(2-sulfanylethoxy)carbonyl]hydrazinyl}carbonyl)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-5-hydroxy-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indol-9-carboxylate
Clinical data
Legal status
  • IND
Identifiers
CAS Registry Number 742092-03-1 Yes
ATC code L01CA06
ChemSpider 27444385 Yes
Synonyms EC-145
Chemical data
Formula C86H109N21O26S2
Molecular mass 1917 g/mol

References

  1.  Sridharan, Balaji (Apr 16, 2012). “Endocyte soars on cancer drug deal with Merck”. Reuters.
  2.  Statement on a nonproprietary name adopted by the USAN Council, United States Adopted Names (USAN) Council, 6 April 2012
  3.  Kuo, Phillip H. (February 2013). “Companion Imaging Diagnostics for Targeted Therapies”. Radiology Today 14 (2): 32.
  4.  “Merck, Endocyte in Development Deal”. Drug Development & Discovery magazine. 2012-04-25.
  5.  Dosio, F.; Milla, P.; Cattel, L. (2010). “EC-145, a folate-targeted Vinca alkaloid conjugate for the potential treatment of folate receptor-expressing cancers”. Current opinion in investigational drugs (London, England : 2000) 11 (12): 1424–1433. PMID 21154124. edit
  6.  “EMA Accepts For Review MAA Filings For Vintafolide And Etarfolatide”. rttnews.com. 2012-11-27.
  7.  Garde, Damian (2014-05-02). “Merck halts study of the billion-dollar cancer drug vintafolide”. Fierce Biotech. Retrieved 21 April 2015.
  8.  “Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay” 338 (2). March 2005. pp. 284–93. doi:10.1016/j.ab.2004.12.026.PMID 15745749.
  9. WO2008098970A1 * Feb 13, 2008 Aug 21, 2008 Pf Medicament Anhydrous crystalline vinflunine salts, method of preparation and use thereof as a drug and means of vinflunine purification
    WO2010150100A1 * Jun 23, 2010 Dec 29, 2010 Entarco Sa The use of spinosyns and spinosyn compositions against diseases caused by protozoans, viral infections and cancer
    WO2011014821A1 * Jul 30, 2010 Feb 3, 2011 Endocyte, Inc. Folate-targeted diagnostics and treatment
    US20100247669 *
    Sep 30, 2010 Cerulean Pharma Inc. Polymer-agent conjugates, particles, compositions, and related methods of use
////////Vintafolide, BMS-753493, DAVBLH,  Desacetylvinblastine hydrazide, EC-145 , MK-8109 , phase 2