AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Genistein

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Jun 102016
 

Genistein.svg

Genistein

5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; Baichanin A; Bonistein; 4’,5,7-Trihydroxyisoflavone; GeniVida; Genisteol; NSC 36586; Prunetol; Sophoricol;

CAS Number: 446-72-0
 BIO-300; G-2535; PTI-G-4660; SIPI-9764-I; PTIG-4660; SIPI-9764I
Molecular form.: C₁₅H₁₀O₅
Appearance: Light Tan to Light Yellow Solid
Melting Point: >277°C (dec.)
Mol. Weight: 270.24

Genistein , an isoflavone found in many Fabaceae plants and important non-nutritional constituent of soybeans (Glycine max Merill), is a well-known plant metabolite from phenylpropanoid pathway, chiefly because of its presence in numerous phytoestrogenic dietary supplements. In fact, the compound also strives for higher medicinal status, undergoing dozens of clinical trials for various ailments, from osteoporosis to cancer

IR (KBr, cm–1; inter alia): 3411, 3104, 1651, 1615, 1570, 1519, 1504, 1424, 1361, 1309, 1202, 1179, 1145, 1043, 911, 840, 790.
1H NMR (200 MHz, THF-d8), δ (ppm): 6.17 (d, J = 2,2 Hz, 1H); 6.26 (d, J = 2,2 Hz, 1H); 6.78 (m, 2H); 7.41 (m, 2H); 8.02 (s, 1H); 8.50 (bs, 1H); 9.34 (bs, 1H); 13.02 (s, 1H).
13C NMR (THF-d8), δ (ppm): 94.13; 99.73; 106.20; 115.82; 122.95; 124.17; 130.84; 153.78; 158.73; 159.08; 164.24; 165.16; 181.46.
 

An EGFR/DNA topoisomerase II inhibitor potentially for the treatment of bladder cancer and prostate cancer.

NMR

Genistein; CAS: 446-72-0

REF http://www.wangfei.ac.cn/nmrspectra/7/1/30

SEE https://www.google.com/patents/EP2373326A1?cl=en

Genistein is an angiogenesis inhibitor and a phytoestrogen and belongs to the category of isoflavones. Genistein was first isolated in 1899 from the dyer’s broom, Genista tinctoria; hence, the chemical name. The compound structure was established in 1926, when it was found to be identical with prunetol. It was chemically synthesized in 1928.[1]

Natural occurrences

Isoflavones such as genistein and daidzein are found in a number of plants including lupin, fava beans, soybeans, kudzu, andpsoralea being the primary food source,[2][3] also in the medicinal plants, Flemingia vestita[4] and F. macrophylla,[5][6] and coffee.[7] It can also be found in Maackia amurensis cell cultures.[8]

Extraction and purification

Most of the isoflavones in plants are present in a glycosylated form. The unglycosylated aglycones can be obtained through various means such as treatment with the enzyme β-glucosidase, acid treatment of soybeans followed by solvent extraction, or by chemical synthesis.[9] Acid treatment is a harsh method as concentrated inorganic acids are used. Both enzyme treatment and chemical synthesis are costly. A more economical process consisting of fermentation for in situ production of β-glucosidase to isolate genistein has been recently investigated.[10]

 

Biological effects

Besides functioning as antioxidant and anthelmintic, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Isoflavones also produce non-hormonal effects.

Molecular function

Genistein influences multiple biochemical functions in living cells:

Activation of PPARs

Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms, α, δ, and γ.[18] For example, membrane-bound PPARγ-binding assay showed that genistein can directly interact with the PPARγ ligand binding domain and has a measurable Ki of 5.7 mM.[19] Gene reporter assays showed that genistein at concentrations between 1 and 100 uM activated PPARs in a dose dependent way in KS483 mesenchymal progenitor cells, breast cancer MCF-7 cells, T47D cells and MDA-MD-231 cells, murine macrophage-like RAW 264.7 cells, endothelial cells and in Hela cells. Several studies have shown that both ERs and PPARs influenced each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.[18][20][21]

Tyrosine kinase inhibitor

The main known activity of genistein is tyrosine kinase inhibitor, mostly of epidermal growth factor receptor (EGFR). Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades.

Redox-active — not only antioxidant

Genistein may act as direct antioxidant, similar to many other isoflavones, and thus may alleviate damaging effects of free radicals in tissues.[22][23]

The same molecule of genistein, similar to many other isoflavones, by generation of free radicals poison topoisomerase II, an enzyme important for maintaining DNA stability.[24][25][26]

Human cells turn on beneficial, detoxyfying Nrf2 factor in response to genistein insult. This pathway may be responsible for observed health maintaining properities of small doses of genistein.[27]

Anthelmintic

The root-tuber peel extract of the leguminous plant Felmingia vestita is the traditional anthelmitic of the Khasi tribes of India. While investigating its anthelmintic activity, genistein was found to be the major isoflavone responsible for the deworming property.[4][28] Genistein was subsequently demonstrated to be highly effective against intestinal parasitessuch as the poultry cestode Raillietina echinobothrida,[28] the pork trematode Fasciolopsis buski,[29] and the sheep liver fluke Fasciola hepatica.[30] It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and glycogenolysis,[31][32] and disturbing the Ca2+ homeostasis and NO activity in the parasites.[33][34] It has also been investigated inhuman tapeworms such as Echinococcus multilocularis and E. granulosus metacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.[35]

Atherosclerosis

Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte–endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis.[36]

Cancer links

Genistein and other isoflavones have been identified as angiogenesis inhibitors, and found to inhibit the uncontrolled cell growth of cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Various studies have found that moderate doses of genistein have inhibitory effects on cancersof the prostate,[37][38] cervix,[39] brain,[40] breast[37][41][42] and colon.[16] It has also been shown that genistein makes some cells more sensitive to radio-therapy.;[43] although, timing of phytoestrogen use is also important. [43]

Genistein’s chief method of activity is as a tyrosine kinase inhibitor. Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein.[25][44] Genistein has been used to selectively target pre B-cells via conjugation with an anti-CD19 antibody.[45]

Studies on rodents have found genistein to be useful in the treatment of leukemia, and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.[46]

Estrogen receptor — more cancer links

Due to its structure similarity to 17β-estradiol (estrogen), genistein can compete with it and bind to estrogen receptors. However, genistein shows much higher affinity towardestrogen receptor β than toward estrogen receptor α.[47]

Data from in vitro and in vivo research confirms that genistein can increase rate of growth of some ER expressing breast cancers. Genistein was found to increase the rate of proliferation of estrogen-dependent breast cancer when not cotreated with an estrogen antagonist.[48][49][50] It was also found to decrease efficiency of tamoxifen and letrozole – drugs commonly used in breast cancer therapy.[51][52] Genistein was found to inhibit immune response towards cancer cells allowing their survival.[53]

Effects in males

Isoflavones can act like estrogen, stimulating development and maintenance of female characteristics, or they can block cells from using cousins of estrogen. In vitro studies have shown genistein to induce apoptosis of testicular cells at certain levels, thus raising concerns about effects it could have on male fertility;[54] however, a recent study found that isoflavones had “no observable effect on endocrine measurements, testicular volume or semen parameters over the study period.” in healthy males given isoflavone supplements daily over a 2-month period.[55]

Carcinogenic and toxic potential

Genistein was, among other flavonoids, found to be a strong topoisomerase inhibitor, similarly to some chemotherapeutic anticancer drugs ex. etoposide and doxorubicin.[24][56]In high doses it was found to be strongly toxic to normal cells.[57] This effect may be responsible for both anticarcinogenic and carcinogenic potential of the substance.[26][58] It was found to deteriorate DNA of cultured blood stem cells, what may lead to leukemia.[59] Genistein among other flavonoids is suspected to increase risk of infant leukemia when consumed during pregnancy.[60][61]

Sanfilippo syndrome treatment

Genistein decreases pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by adequate dose of genistein.[62] Genistein was found to also possess toxic properties toward brain cells.[57] Among many pathways stimulated by genistein, autophagy may explain the observed efficiency of the substance as autophagy is significantly impaired in the disease.[63][64]

Related compounds

Glycosides

Genistin is the 7-O-beta-D-glucoside of genistein.

Acetylated compounds

Wighteone is the 6-isopentenyl genistein (6-prenyl-5,7,4′-trihydroxyisoflavone)[citation needed]

Pharmaceutical derivatives

  • KBU2046 under investigation for prostate cancer.[65][66]
  • B43-genistein, an anti-CD19 antibody linked to genistein e.g. for leukemia.[67]
  • Genistein has two known synthesis routes: deoxybenzoin route and chalcone route. Deoxybenzoin route uses friedel-craft reaction, and chalcone route uses aldol condensation as shown in figure 2. Developing synthesis of genistein allows the access to the affordable therapy as well as mass production of commercial genistein supplements. However, it would be recommended to consult with the health care provider and discuss the pros and cons before the use since the effects of genistein on human body are not fully understood yet as discussed above.


MEDIUM_10555_2010_9238_Fig2_HTML.jpg
Figure 2. Synthesis of genistein via deoxybenzoin route or chalcone route. 10

https://chemprojects263sp11.wikispaces.com/genistein

Paper

Identification of Benzopyran-4-one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors
ChemMedChem (2011), 6, (8), 1340-1346

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100120/abstract

 

PATENT

By Achmatowicz, Osman et al

From Pol., 204473

STR1

 

References

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  52. Jump up^ Tonetti, Debra A.; Zhang, Yiyun; Zhao, Huiping; Lim, Sok-Bee; Constantinou, Andreas I. (2007). “The Effect of the Phytoestrogens Genistein, Daidzein, and Equol on the Growth of Tamoxifen-Resistant T47D/PKCα”. Nutrition and Cancer 58 (2): 222–9.doi:10.1080/01635580701328545. PMID 17640169.
  53. Jump up^ Jiang, Xinguo; Patterson, Nicole M.; Ling, Yan; Xie, Jianwei; Helferich, William G.; Shapiro, David J. (2008). “Low Concentrations of the Soy Phytoestrogen Genistein Induce Proteinase Inhibitor 9 and Block Killing of Breast Cancer Cells by Immune Cells”.Endocrinology 149 (11): 5366–73. doi:10.1210/en.2008-0857. PMC 2584580.PMID 18669594.
  54. Jump up^ Kumi-Diaka, James; Rodriguez, Rosanna; Goudaze, Gould (1998). “Influence of genistein (4′,5,7-trihydroxyisoflavone) on the growth and proliferation of testicular cell lines”. Biology of the Cell 90 (4): 349–54. doi:10.1016/S0248-4900(98)80015-4.PMID 9800352.
  55. Jump up^ Mitchell, Julie H.; Cawood, Elizabeth; Kinniburgh, David; Provan, Anne; Collins, Andrew R.; Irvine, D. Stewart (2001). “Effect of a phytoestrogen food supplement on reproductive health in normal males”. Clinical Science 100 (6): 613–8. doi:10.1042/CS20000212.PMID 11352776.
  56. Jump up^ Lutz, Werner K.; Tiedge, Oliver; Lutz, Roman W.; Stopper, Helga (2005). “Different Types of Combination Effects for the Induction of Micronuclei in Mouse Lymphoma Cells by Binary Mixtures of the Genotoxic Agents MMS, MNU, and Genistein”. Toxicological Sciences 86 (2): 318–23. doi:10.1093/toxsci/kfi200. PMID 15901918.
  57. ^ Jump up to:a b Jin, Ying; Wu, Heng; Cohen, Eric M.; Wei, Jianning; Jin, Hong; Prentice, Howard; Wu, Jang-Yen (2007). “Genistein and daidzein induce neurotoxicity at high concentrations in primary rat neuronal cultures”. Journal of Biomedical Science 14 (2): 275–84.doi:10.1007/s11373-006-9142-2. PMID 17245525.
  58. Jump up^ Schmidt, Friederike; Knobbe, Christiane; Frank, Brigitte; Wolburg, Hartwig; Weller, Michael (2008). “The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines”. Oncology Reports 19 (4): 1061–6.doi:10.3892/or.19.4.1061. PMID 18357397.
  59. Jump up^ van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh; Janssen, Jannie; Maas, Lou M.; Godschalk, Roger W. L.; Nijhuis, Jan G.; van Schooten, Frederik J. (2007). “Dietary flavonoids induce MLL translocations in primary human CD34+ cells”. Carcinogenesis 28(8): 1703–9. doi:10.1093/carcin/bgm102. PMID 17468513.
  60. Jump up^ Spector, Logan G.; Xie, Yang; Robison, Leslie L.; Heerema, Nyla A.; Hilden, Joanne M.; Lange, Beverly; Felix, Carolyn A.; Davies, Stella M.; Slavin, Joanne; Potter, John D.; Blair, Cindy K.; Reaman, Gregory H.; Ross, Julie A. (2005). “Maternal Diet and Infant Leukemia: The DNA Topoisomerase II Inhibitor Hypothesis: A Report from the Children’s Oncology Group”. Cancer Epidemiology Biomarkers & Prevention 14 (3): 651–5. doi:10.1158/1055-9965.EPI-04-0602. PMID 15767345.
  61. Jump up^ Azarova, Anna M.; Lin, Ren-Kuo; Tsai, Yuan-Chin; Liu, Leroy F.; Lin, Chao-Po; Lyu, Yi Lisa (2010). “Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia”. Biochemical and Biophysical Research Communications 399 (1): 66–71. doi:10.1016/j.bbrc.2010.07.043.PMC 3376163. PMID 20638367.
  62. Jump up^ Piotrowska, Ewa; Jakóbkiewicz-Banecka, Joanna; Barańska, Sylwia; Tylki-Szymańska, Anna; Czartoryska, Barbara; Węgrzyn, Alicja; Węgrzyn, Grzegorz (2006). “Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses”. European Journal of Human Genetics 14(7): 846–52. doi:10.1038/sj.ejhg.5201623. PMID 16670689.
  63. Jump up^ Ballabio, A. (2009). “Disease pathogenesis explained by basic science: Lysosomal storage diseases as autophagocytic disorders”. International Journal of Clinical Pharmacology and Therapeutics 47 (Suppl 1): S34–8. doi:10.5414/cpp47034.PMID 20040309.
  64. Jump up^ Settembre, Carmine; Fraldi, Alessandro; Jahreiss, Luca; Spampanato, Carmine; Venturi, Consuelo; Medina, Diego; de Pablo, Raquel; Tacchetti, Carlo; Rubinsztein, David C.; Ballabio, Andrea (2007). “A block of autophagy in lysosomal storage disorders”. Human Molecular Genetics 17 (1): 119–29. doi:10.1093/hmg/ddm289. PMID 17913701.
  65. Jump up^ Xu, Li; Farmer, Rebecca; Huang, Xiaoke; Pavese, Janet; Voll, Eric; Irene, Ogden; Biddle, Margaret; Nibbs, Antoinette; Valsecchi, Matias; Scheidt, Karl; Bergan, Raymond (2010). “Abstract B58: Discovery of a novel drug KBU2046 that inhibits conversion of human prostate cancer to a metastatic phenotype”. Cancer Prevention Research 3 (12 Supplement): B58. doi:10.1158/1940-6207.PREV-10-B58.
  66. Jump up^ “New Drug Stops Spread of Prostate Cancer” (Press release). Northwestern University. April 3, 2012. Retrieved September 27, 2014.
  67. Jump up^ Chen, Chun-Lin; Levine, Alexandra; Rao, Asha; O’Neill, Karen; Messinger, Yoav; Myers, Dorothea E.; Goldman, Frederick; Hurvitz, Carole; Casper, James T.; Uckun, Fatih M. (1999). “Clinical Pharmacokinetics of the CD19 Receptor-Directed Tyrosine Kinase Inhibitor B43-Genistein in Patients with B-Lineage Lymphoid Malignancies”. The Journal of Clinical Pharmacology 39 (12): 1248–55. doi:10.1177/00912709922012051. PMID 10586390.

External links

 

 

Abstract Image

Development and scale-up of the synthetic process for genistein preparation are described. The process was designed with consideration for environmental and economical aspects and optimized in a laboratory scale. In a scale up, on every step quantity of the environmentally unfriendly substrates or solvents was reduced without compromising the quality of the final product, and the waste load was significantly diminished. The optimal duration times of the individual stages were determined, and the number of operations was reduced, leading to lowering of energy consumption. Elaborated process secures good yield and quality expected for pharmaceutical substances.

Technical Process for Preparation of Genistein

Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00425
Publication Date (Web): June 03, 2016
Copyright © 2016 American Chemical Society

 

Genistein
Genistein.svg
Genistein molecule
Names
IUPAC name

5,7-Dihydroxy-3-(4-hydroxyphenyl)chromen-4-one
Other names

4′,5,7-Trihydroxyisoflavone
Identifiers
446-72-0 Yes
ChEBI CHEBI:28088 Yes
ChEMBL ChEMBL44 Yes
ChemSpider 4444448 Yes
DrugBank DB01645 Yes
2826
Jmol 3D model Interactive image
KEGG C06563 Yes
PubChem 5280961
UNII DH2M523P0H Yes
Properties
C15H10O5
Molar mass 270.24 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Akiyama, T., et al.: J. Biol. Chem., 262, 5592 (1987), O’Dell, T.J., et al.: Nature, 353, 588 (1991), Aharonovits, O., et al.: Biochim Biophys. Acta, 1112, 181 (1992), Platanias, L.C., et al.: J. Biol. Chem., 267, 24053 (1992), Yoshida, H., et al.: Biochim. Biophys. Acta, 1137, 321 (1992), Uckun, F.M., et al.: Science, 267, 886 (1995), Merck Index 12th ed. 4395, Huang, R.Q.; Fang, M.J.; Dillon, G.H., Mol. Brain Res. 67: 177-183 (1999)

 

//////BIO-300,  G-2535,  PTI-G-4660,  SIPI-9764-I,  PTIG-4660,  SIPI-9764I, Genistein, phase 2, national cancer institute

Oc1ccc(cc1)C\3=C\Oc2cc(O)cc(O)c2C/3=O

Supporting Info

 

Start of the Euro 2016

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ND 630, NDI 010976

 Uncategorized  Comments Off on ND 630, NDI 010976
Jun 102016
 

str1

 

ndi molecul
str1
ND 630, NDI 010976,  ND-630, NDI-010976
1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid
2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid
2-[1-[(2R)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid
CAS 1434635-54-7
Thieno[2,​3-​d]​pyrimidine-​3(2H)​-​acetic acid, 1,​4-​dihydro-​1-​[(2R)​-​2-​(2-​methoxyphenyl)​-​2-​[(tetrahydro-​2H-​pyran-​4-​yl)​oxy]​ethyl]​-​α,​α,​5-​trimethyl-​6-​(2-​oxazolyl)​-​2,​4-​dioxo-
Molecular Formula: C28H31N3O8S
Molecular Weight: 569.62604 g/mol
Company Nimbus Therapeutics LLC
Description Small molecule allosteric inhibitor of acetyl-coenzyme A carboxylase alpha (ACACA; ACC1) and acetyl-coenzyme A carboxylase beta (ACACB; ACC2)
Molecular Target Acetyl-Coenzyme A carboxylase alpha (ACACA) (ACC1) ; Acetyl-Coenzyme A carboxylase beta (ACACB) (ACC2)
Mechanism of Action Acetyl-coenzyme A carboxylase alpha (ACACA) (ACC1) inhibitor; Acetyl-coenzyme A carboxylase beta (ACACB) (ACC2) inhibitor
Therapeutic Modality Small molecule
Preclinical Diabetes mellitus; Hepatocellular carcinoma; Metabolic syndrome; Non-alcoholic steatohepatitis; Non-small cell lung cancer
CHEMBL3407547.png

Acetyl CoA carboxylase 1/2 allosteric inhibitors – Nimbus Therapeutics

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting, San Francisco, CA, USA

Nimbus compounds targeting liver disease in rat models

Data were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND-630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively, EC50 values in HepG2 serum free and 10% serum of 9 and 66 nM, respectively, and 2-fold C2C12 fatty acid oxidation (FAOxn) stimulation at 200 nM. Rat FASyn (synthase), malonyl-CoA (liver) and malonyl-COA (muscle) respective ED50 values were 0.14 mg/kg po, 0.8 and 3 mg/kg. The rat respiratory quotient (RQ) MED was 3 mg/kg po. ADME data showed low multispecies intrinsic clearance (human, mouse, rat, dog, monkey). NDI-010976 was eliminated predominantly as the parent drug. Additionally, P450 inhibition was > 50 microM. In liver and muscle, NDI-010976 modulated key metabolic parameters including a dose-dependent reduction in the formation of the enzymatic product of acetyl coA carboxyloase malonyl coA; the ED50 value was lower in muscle. The drug also decreased FASyn dose dependently and increased fatty acid oxidation in the liver (EC50 = 0.14 mg/kg). In 28-day HS DIO rats, NDI-010976 favorably modulated key plasma and liver lipids, including decreasing liver free fatty acid, plasma triglycerides and plasma cholesterol; this effect was also seen in 37-day ZDF rats

 PATENT

http://www.google.com/patents/WO2013071169A1?cl=en

 

Example 76: Synthesis of 2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid (1-181).

Figure imgf000193_0001

Synthesis of compound 76.1. Into a 250-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed oxan-4-ol (86 g, 842.05 mmol, 2.01 equiv) and FeCl3 (10 g). This was followed by the addition of 57.2 (63 g, 419.51 mmol, 1.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 500 mL of H20. The resulting solution was extracted with 3×1000 mL of ethyl acetate and the organic layers combined. The resulting solution was extracted with 3×300 mL of sodium chloride (sat.) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 22 g (21%) of 76.1 as a white solid.

Synthesis of compound 76.2. The enantiomers of 76.1 (22g) were resolved by chiral preparative HPLC under the following conditions (Gilson Gx 281): Column: Venusil Chiral OD-

H, 21.1 *25 cm, 5 μιη; mobile phase: hexanes (0.2% TEA) and ethanol (0.2% TEA) (hold at 10% ethanol (0.2%TEA) for 13 min); detector: UV 220/254 nm. 11.4 g (52%) of 76.2 were obtained as a white solid.

Synthesis of compound 76.3. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 70.1 (12 g, 20.49 mmol, 1.00 equiv), tetrahydrofuran (200 mL), 76.2 (6.2 g, 24.57 mmol, 1.20 equiv) and DIAD (6.5 g, 32.18 mmol, 1.57 equiv). This was followed by the addition of a solution of triphenylphosphane (8.4 g, 32.03 mmol, 1.56 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at 0 °C in 60 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 17 g (crude) of 76.3 as a white solid.

Synthesis of compound 76.4. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 76.3 (17 g, crude), toluene (300 mL), Pd(PPh3)4 (1.7 g, 1.47 mmol, 0.07 equiv) and 2-(tributylstannyl)-l,3-oxazole (8.6 g, 24.02 mmol, 1.16 equiv). The resulting solution was stirred overnight at 110 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). Purification afforded 6 g of 76.4 as a white solid.

Synthesis of compound 1-181. Into a 250-mL 3-necked round-bottom flask, was placed 76.4 (6 g, 7.43 mmol, 1.00 equiv), tetrahydrofuran (100 mL), TBAF (2.3 g, 8.80 mmol,

I .18 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50: 1). This resulted in 3.4 g (80%) of Compound 1-181 as a white solid.

Purification: MS (ES): m/z 570 (M+H)+, 592 (M+Na)+.

1H NMR (300 MHz, DMSO- d6): δ 1.22-1.36 (m, 2H), 1.62 (m, 8H), 2.75 (s, 3H), 3.20-3.39 (m, 3H), 3.48-3.58 (m, 2H), 3.80 (s, 3H), 3.85-4.20 (m, 2H), 5.30 (m, 1H), 7.03 (m, 2H), 7.33-7.50 (m, 3H), 8.2 (s, 1H).

Figure imgf000193_0001

ndi molecul

Preparation of ND-630.1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid, ND-630, was prepared as described (49)…….http://www.pnas.org/content/113/13/E1796.full.pdf
Harriman GC, Masse CE, Harwood HJ, Jr, Baht S, Greenwood JR (2013) Acetyl-CoA
carboxylase inhibitors and uses thereof. US patent publication US 2013/0123231.
CLIPS

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting,  San Francisco, CA, USA

Conference: 66th Annual Meeting of the American Association for the Study of Liver Diseases Conference Start Date: 13-Nov-2015

…candidates for minimizing IR injury in liver transplantation.Nimbus compounds targeting liver disease in rat modelsData were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND–630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively…

REFERENCES

November 13-17 2015
The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting  San Francisco, CA, USA ,
WO-2014182943

WO-2014182951 

WO-2014182945

WO-2014182950 

Patent ID Date Patent Title
US2015203510 2015-07-23 ACC INHIBITORS AND USES THEREOF
US2013123231 2013-05-16 ACC INHIBITORS AND USES THEREOF

/////// ND 630, NDI 010976,  ND-630, NDI-010976, NIMBUS, GILEAD, 1434635-54-7

O=C(O)C(C)(C)N4C(=O)c1c(C)c(sc1N(C[C@H](OC2CCOCC2)c3ccccc3OC)C4=O)c5ncco5

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Pexidartinib

 orphan status, Phase 3 drug, Uncategorized  Comments Off on Pexidartinib
Jun 102016
 

Pexidartinib

PLX-3397

5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine

N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine

Phase III

A Multi-targeted tyrosine kinase inhibitor potentially for the treatment of tenosynovial giant cell tumor (TGCT).

CAS No.: 1029044-16-3
Mol. Formula: C20H15ClF3N5
Mol. Weight: 417.81
  • Pexidartinib; 1029044-16-3; PLX-3397; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine; 5-[(5-Chloro-1h-Pyrrolo[2,3-B]pyridin-3-Yl)methyl]-N-{[6-(Trifluoromethyl)pyridin-3-Yl]methyl}pyridin-2-Amine;
  • Originator Plexxikon
  • Developer Barbara Ann Karmanos Cancer Institute; Columbia University; Merck & Co; National Cancer Institute (USA); Plexxikon; University of California at San Francisco
  • Class 2 ring heterocyclic compounds; Antineoplastics; Fluorine compounds; Pyridines; Pyrroles; Small molecules
  • Mechanism of Action Fms-like tyrosine kinase 3 inhibitors; Immunomodulators; Macrophage colony stimulating factor receptor antagonists; Proto oncogene protein c-akt inhibitors; Proto oncogene protein c-kit inhibitors
  • Orphan Drug Status Yes – Giant cell tumour of tendon sheath; Pigmented villonodular synovitis
  • Phase III Pigmented villonodular synovitis
  • Phase II Glioblastoma; Malignant melanoma; Prostate cancer
  • Phase I/II Breast cancer; Leukaemia; Peripheral nervous system diseases; Sarcoma; Solid tumours
  • Phase I Gastrointestinal stromal tumours
  • No development reported Neurological disorders; Rheumatoid arthritis
  • Discontinued Acute myeloid leukaemia; Hodgkin’s disease

Most Recent Events

  • 25 May 2016 Plexxikon and AstraZeneca plan the MEDIPLEX phase I trial for Solid tumours (Combination therapy, Metastatic disease) in France (NCT02777710)
  • 05 Apr 2016 Daiichi Sankyo plans a phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in Taiwan (PO) (NCT02734433)
  • 11 Mar 2016 Plexxikon re-initiates enrolment in a phase Ib trial in Solid tumours and Gastrointestinal stromal tumours in USA (NCT02401815)

 

Multi-targeted receptor tyrosine kinase inhibitor of CSF1R, c-Kit, and FLT3 (IC50 values 13 nM, 27 nM, and 11 nM, respectively) Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

Plexxikon is conducting phase III clinical studies with PLX-3397 for the treatment of pigmented villonodular synovitis. Phase II clinical studies are ongoing for the oral treatment of melanoma and glioblastoma multiforme. Additional early clinical trials are underway for the treatment of metastatic breast cancer, for the treatment of prostate cancer (adenocarcinoma), and for the treatment of malignant peripheral nerve sheath tumor. No recent development has been reported from preclinical studies for the treatment of systemic lupus erythematosus and for the treatment of multiple sclerosis. Prior to patient enrollment, a phase I clinical trial by Plexxikon for the treatment of rheumatoid arthritis was withdrawn. Daiichi Sankyo (parent of Plexxikon) decided to discontinue phase II trials of the product for the treatment of castration-resistant prostate cancer and for the treatment of Hodgkin’s lymphoma after reviewing its clinical study results and also have discontinued phase II studies for the treatment of acute myeloid leukemia due to strategic reasons.

Pexidartinib.png

In 2014, orphan drug designation was assigned to the compound in the US for the treatment of pigmented villonodular synovitis andf giant cell tumor of the tendon sheath. In 2015, the compound was granted orphan designation in the E.U. for the treatment of tenosynovial giant cell tumor, localised and diffuse type. In the same year, the product was granted breakthrough therapy designation for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity.

C-fms and c-kit arc both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.

c-Fms
C-fms is a member of the family of genes originally isolated from the Susan McDonough strain ot teline sarcoma viruses, The cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimuktmg tactor (M- CSF) C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of Vf-CSF to the extracellular domain of c-fms, the receptor dimeπzes and trans- autophosphorylates cytoplasmic tyrosine residues

M-CSF, first described by Robinson and co-workers (Blood 1969, 33 396-9), is a cytokine that controls the production, differentiation, and function of macrophages M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemota\is, and secondary cytokine production of additional factors in monocytes and macrophages Examples of such additional factors include granulocyte colony stimulating lactor (G-CSF) interleukin-6 (IL-6), and mterleukm-8 (IL-8) M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism Furthermore, M-CSF is important in pregnancy Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, lnt J Hematol 1998, 67 109-22) l hc elevated semm levels of M-CSF m early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opm Hematol 1998, 5 181-5)

Related to c-fms and c-kit are two p_latelet -derived growth factor receptors, alpha (i e , pdgfra) and beta (pdgfrb) (PDGF) 1 he gene coding for pdgfra is located on chromosome 4ql 1 -q!2 in the same region of chromosome 4 as the oncogene coding for c-kit The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5 They are oriented head to tail with the 5-pnme exon of the c-fms gene located only 500 bp from the last 3-pπme exon of the gene coding for pdgfra Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit and most patients with GISTs respond well to Gleevec, which inhibits c-kit Hemπch et al (Science 2003, 299 “OS-IO) have shown that approximately 35% of GISTs lacking c-krt mutations, have intragenic activation mutations m tht gene encoding pdgfra, and that tumors expressing c-kit or pdgfrd are indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression Thus, c kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms m GISTs [0007} Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-frns in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit
The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the Sl locus, and has also been called “kit ligand” (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al,, Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90: 1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91 : 1 101 -1 134.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.

SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form, a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.

 

 

STR1

PATENT

WO 2008063888

 

PATENT

WO 2008064265

 

PATENT

WO 2008064255

PATENT

WO 2012158957

Fragments in the clinic: PLX3397

Practical Fragments covers a wide variety of journals. J. Med. Chem., Bioorg. Med. Chem. Lett., Drug Disc. Today, and ACS Med. Chem. Lett. are all well-represented, but we also range further afield, from biggies such asNature and Science to more niche titles such as ChemMedChem, Acta. Cryst. D., and Anal. Chim. Acta. The increasingly clinical relevance of fragment-based approaches is highlighted by a recent paper by William Tap and a large group of collaborators appearing in the New England Journal of Medicine. This reports on the results of the Daiichi Sankyo (née Plexxikon) drug PLX3397 in a phase I trial for tenosynovial giant-cell tumor, a rare but aggressive cancer of the tendon sheath.

The story actually starts with a 2013 paper by Chao Zhang and his Plexxikon colleagues in Proc. Nat. Acad. Sci. USA. The researchers were interested in inhibiting the enzymes CSF1R (or FMS) and KIT; both kinases are implicated in cancer as well as inflammatory diseases. The team started with 7-azaindole, the same fragment they used to discover vemurafenib. Structural studies of an early derivative, PLX070, revealed a hydrogen bond between the ligand oxygen and a conserved backbone amide. Further building led to PLX647, with good activity against both CSF1R and KIT. Selectivity profiling against a panel of 400 kinases revealed only two others with IC50values < 0.3 µM. The molecule was active in cell-based assays, had good pharmacokinetics in mice and rats, and was active in rodent models of inflammatory disease.

The new paper focuses on the results of a clinical trial with PLX3397, a derivative of PLX647. Despite its close structural similarity to PLX647, it binds to CSF1R in a slightly different manner. Both inhibitors bind to the inactive form of the kinase, but PLX3397 also recruits the so-called juxtamembrane domain of the kinase to stabilize this autoinhibited conformation. Pharmacokinetic and pharmacodynamics studies in animals were also positive.

http://practicalfragments.blogspot.in/2015/10/fragments-in-clinic-plx3397.html

Tenosynovial giant-cell tumor seems to be dependent on CSF1R, so the researchers performed a phase 1 dose-escalation study with an extension in which patients treated with the chosen phase 2 dose were treated longer. Of the 23 patients in this extension, 12 had a partial response and 7 had stable disease. A quick search ofclinicaltrials.gov reveals that PLX3397 is currently in multiple trials for several indications, including a phase 3 trial for giant cell tumor of the tendon sheath.

Several lessons can be drawn from these studies. First, as the authors note, one fragment can give rise to multiple different clinical candidates. Indeed, in addition to vemurafenib, 7-azaindole was also the starting point forAZD5363. This is a good counterargument to those who believe that novelty is essential in fragments.

A second, related point is that selectivity is also not necessary for a fragment. The fact that 7-azaindole comes up so frequently as a kinase-binding fragment has not prevented researchers from growing it into remarkably selective inhibitors. An obvious corollary is that even subtle changes to a molecule can have dramatic effects: the added pyridyl nitrogen in PLX3397 is essential for stabilizing a unique conformation of the enzyme.

 

Patent ID Date Patent Title
US2015265586 2015-09-24 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US2014243365 2014-08-28 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US8722702 2014-05-13 Compounds modulating c-fms and/or c-kit activity and uses therefor
US2014045840 2014-02-13 COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
US2013274259 2013-10-17 KINASE MODULATION AND INDICATIONS THEREFOR
US8404700 2013-03-26 Compounds modulating c-fms and/or c-kit activity and uses therefor
US2011230482 2011-09-22 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
US7893075 2011-02-22 Compounds modulating c-fms and/or c-kit activity and uses therefor

//////1029044-16-3, Pexidartinib , PLX-3397, PHASE3

FC(F)(F)c1ccc(cn1)CNc2ccc(cn2)Cc4cnc3ncc(Cl)cc34

Start of the Euro 2016

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Gilteritinib for Treatment of Acute Myeloid Leukemia

 Phase 3 drug, Uncategorized  Comments Off on Gilteritinib for Treatment of Acute Myeloid Leukemia
Jun 102016
 

Gilteritinib

ASP-2215

Treatment of Acute Myeloid Leukemia

6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine-2-carboxamide

C29H44N8O3, 552.71

Phase III

A FLT3/AXL inhibitor potentially for the treatment of acute myeloid leukemia.

CAS No. 1254053-43-4

Astellas Pharma  INNOVATOR
Mechanism Of Action Axl receptor tyrosine kinase inhibitors, Fms-like tyrosine kinase 3 inhibitors, Proto oncogene protein c-kit inhibitors
Who Atc Codes L01X-E (Protein kinase inhibitors)
Ephmra Codes L1H (Protein Kinase Inhibitor Antineoplastics)
Indication Cancer, Hepatic impairment

Gilteritinib(ASP-2215) is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/<1 nM respectively; shows potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations.
IC50 value: 0.29 nM(FLT3); <1 nM(Axl kinase)
Target: FLT3/AXL inhibitor
ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.

SYNTHESIS

STR1

PATENT

WO 2010128659

 

Patent

WO 2015119122

Compound A is 6-ethyl-3 – ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- a (tetrahydro -2H- pyran-4-ylamino) pyrazine-2-carboxamide, its chemical structure is shown below.
[Formula 1]

Gilteritinib fumarate

1254053-84-3.png

2D chemical structure of 1254053-84-3

Gilteritinib fumarate [USAN]

RN: 1254053-84-3

UNII: 5RZZ0Z1GJT

2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-, (2E)-2-butenedioate (2:1)

  • ASP-2215 hemifumarate
  • Molecular Formula, 2C29-H44-N8-O3.C4-H4-O4, Molecular Weight, 1221.5108

Astellas Inititaties Phase 3 Registration Trial of gilteritinib (ASP2215) in Relapsed or Refractory Acute Myeloid Leukemia Patients

gilteritinib-ASP2215

TOKYO, Japan I October 28, 2015 I Astellas Pharma Inc. (TSE:4503) today announced dosing of the first patient in a randomized Phase 3 registration trial of gilteritinib (ASP2215)versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS).

Gilteritinibis a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinibhas demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.

The gilteritinib Phase 3 trial follows a Phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the Phase 1/2 trial presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated a 57.5 percent overall response rate and a 47.2 percent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10%) observed in the study were diarrhea (13.4%), fatigue (12.4%) and AST increase (11.3%). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.

On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE.

About the Phase 3 Study

The Phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with Acute Myeloid Leukemia (AML). The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS. For more information about this trial go to www.clinicaltrials.gov, trial identifier NCT02421939.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib.

About Acute Myeloid Leukemia

Acute myeloid leukemia is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the//www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf” target=”_blank” rel=”nofollow”>American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.

About SAKIGAKE

The SAKIGAKE designation system can shorten the review period in the following three approaches: 1.) Prioritized Consultation 2.) Substantial Pre-application Consultation and 3.) Prioritized Review. Also, the system will promote development with the following two approaches: 4.) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5.) Substantial Post-Marketing Safety Measures.

About Astellas

Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at www.astellas.com/en.

SOURCE: Astellas Pharma

////////1254053-43-4, Gilteritinib, ASP-2215, PHASE 3, ASP 2215, Astellas Pharma, Acute Myeloid Leukemia

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.C(=C/C(=O)O)\C(=O)O

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