Nintedanib
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MedKoo CAT#: 200496

CAS#: 656247-17-5 (free base)

Description: Nintedanib, also known as BIBF 1120, is an orally bioavailable inhibitor of vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). Intedanib selectively binds to and inhibits vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, which may result in the induction of endothelial cell apoptosis; a reduction in tumor vasculature; and the inhibition of tumor cell proliferation and migration. On 11/15/2014 , FDA approved Nintedanib for the treatment of idiopathic pulmonary fibrosis (IPF).


Chemical Structure

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Nintedanib
CAS# 656247-17-5 (free base)

Theoretical Analysis

MedKoo Cat#: 200496
Name: Nintedanib
CAS#: 656247-17-5 (free base)
Chemical Formula: C31H33N5O4
Exact Mass: 539.25325
Molecular Weight: 539.62
Elemental Analysis: C, 69.00; H, 6.16; N, 12.98; O, 11.86

Price and Availability

Size Price Availability Quantity
200.0mg USD 150.0 Same Day
500.0mg USD 250.0 Same Day
1.0g USD 450.0 Same Day
2.0g USD 750.0 Same Day
5.0g USD 1450.0 Same Day
10.0g USD 2250.0 Same Day
50.0g USD 3650.0 2 Weeks
200.0g USD 6650.0 2 Weeks
500.0g USD 10650.0 2 Weeks
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Related CAS #: 656247-18-6 (esylate)   656247-17-5 (free base)   928326-83-4 (free base)    

Synonym: BIBF1120; BIBF 1120; BIBF-1120; Nintedanib. Brand name: Vargatef.

IUPAC/Chemical Name: (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate

InChi Key: XZXHXSATPCNXJR-ZIADKAODSA-N

InChi Code: InChI=1S/C31H33N5O4/c1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38/h4-14,19,32H,15-18,20H2,1-3H3,(H,33,38)/b29-28-

SMILES Code: O=C(C1=CC(NC/2=O)=C(C=C1)C2=C(NC3=CC=C(N(C)C(CN4CCN(C)CC4)=O)C=C3)/C5=CC=CC=C5)OC

Appearance: Yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Nintedanib (BIBF 1120) is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
In vitro activity: To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, a novel kinaseindependent derivative of nintedanib, ΔN was developed. HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion NSH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. Nintedanib induced antiproliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. J Hepatol. 2014 Jul;61(1):89-97. https://pubmed.ncbi.nlm.nih.gov/24657398/
In vivo activity: Since the IC50 value of BIBF 1120 was found to be the lowest for HNE-1 cells, we further evaluated the efficacy of BIBF 1120 in the HNE-1 xenograft model in nude mice, both as a single agent or in combination with cisplatin. The tumor sizes and weights were evaluated. As shown in Figure 2, BIBF 1120 demonstrated significant growth inhibition of NPC tumors in the HNE-1 xenograft model in nude mice as a single agent; the growth was significantly lower than that in the control group. At the same time, BIBF 1120 showed a greater inhibition of tumor growth in the human NPC cell line xenograft model in nude mice when combined with DDP than in the DDP single-agent group or the control group. Body weight reduction was observed in the DDP single-agent group and combination group, and temporary body weight reduction was observed in the BIBF 1120 single-agent group (Figure 3). Drug Des Devel Ther. 2016; 10: 1173–1180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801128/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 5.0 9.3

Preparing Stock Solutions

The following data is based on the product molecular weight 539.62 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. PMID: 18559524. 2. Tai WT, Shiau CW, Li YS, Chang CW, Huang JW, Hsueh TT, Yu HC, Chen KF. Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. J Hepatol. 2014 Jul;61(1):89-97. doi: 10.1016/j.jhep.2014.03.017. Epub 2014 Mar 18. PMID: 24657398. 3. Xue C, Tian Y, Zhang J, Zhao Y, Zhan J, Fang W, Zhang L. Efficacy of BIBF 1120 or BIBF 1120 plus chemotherapy on nasopharyngeal carcinoma in vitro and in vivo. Drug Des Devel Ther. 2016 Mar 15;10:1173-80. doi: 10.2147/DDDT.S96634. PMID: 27042009; PMCID: PMC4801128. 4. Chen WC, Chen NJ, Chen HP, Yu WK, Su VY, Chen H, Wu HH, Yang KY. Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis. Int J Mol Sci. 2020 Jul 2;21(13):4735. doi: 10.3390/ijms21134735. PMID: 32630825; PMCID: PMC7370174.
In vitro protocol: 1. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. PMID: 18559524. 2. Tai WT, Shiau CW, Li YS, Chang CW, Huang JW, Hsueh TT, Yu HC, Chen KF. Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. J Hepatol. 2014 Jul;61(1):89-97. doi: 10.1016/j.jhep.2014.03.017. Epub 2014 Mar 18. PMID: 24657398.
In vivo protocol: 1. Xue C, Tian Y, Zhang J, Zhao Y, Zhan J, Fang W, Zhang L. Efficacy of BIBF 1120 or BIBF 1120 plus chemotherapy on nasopharyngeal carcinoma in vitro and in vivo. Drug Des Devel Ther. 2016 Mar 15;10:1173-80. doi: 10.2147/DDDT.S96634. PMID: 27042009; PMCID: PMC4801128. 2. Chen WC, Chen NJ, Chen HP, Yu WK, Su VY, Chen H, Wu HH, Yang KY. Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis. Int J Mol Sci. 2020 Jul 2;21(13):4735. doi: 10.3390/ijms21134735. PMID: 32630825; PMCID: PMC7370174.

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1: Scagliotti GV, Gaafar R, Nowak A, Vogelzang NJ, Von Wangenheim U, Morsli N, Velema D, Popat S. P2.01: LUME-MeSO: Phase II/III Study of Nintedanib + Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Track: SCLC, Mesothelioma, Thymoma. J Thorac Oncol. 2016 Oct;11(10S):S216. doi: 10.1016/j.jtho.2016.08.075. Epub 2016 Sep 22. PubMed PMID: 27676538.

2: Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S, Hallmann C, du Bois RM. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2016 Sep 26. pii: thoraxjnl-2016-208710. doi: 10.1136/thoraxjnl-2016-208710. [Epub ahead of print] PubMed PMID: 27672117.

3: Chambers DC. Nintedanib for idiopathic pulmonary fibrosis: An Asian perspective. Respirology. 2016 Sep 20. doi: 10.1111/resp.12903. [Epub ahead of print] PubMed PMID: 27651286.

4: Okusaka T, Otsuka T, Ueno H, Mitsunaga S, Sugimoto R, Muro K, Saito I, Tadayasu Y, Inoue K, Loembé AB, Ikeda M. Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment. Cancer Sci. 2016 Sep 14. doi: 10.1111/cas.13077. [Epub ahead of print] PubMed PMID: 27627050.

5: Hughes G, Toellner H, Morris H, Leonard C, Chaudhuri N. Real World Experiences: Pirfenidone and Nintedanib are Effective and Well Tolerated Treatments for Idiopathic Pulmonary Fibrosis. J Clin Med. 2016 Sep 2;5(9). pii: E78. doi: 10.3390/jcm5090078. Review. PubMed PMID: 27598213.

6: Quintela-Fandino M, Lluch A, Manso LM, Calvo I, Cortes J, García-Saenz JA, Gil JM, Martinez-Jañez N, González-Martín A, Adrover E, De Andres R, Viñas G, Llombart Cussac A, Alba E, Guerra J, Bermejo B, Zamora E, Moreno-Anton F, Pernas-Simon S, Carrato A, Lopez A, Escudero MJ, Campo R, Carrasco EM, Palacios J, Mulero F, Colomer R. 18F-fluoromisonidazole PET and activity of neoadjuvant nintedanib in early HER2-negative breast cancer: a window-of-opportunity randomized trial. Clin Cancer Res. 2016 Sep 1. pii: clincanres.0738.2016. [Epub ahead of print] PubMed PMID: 27587436.

7: Hibi M, Kaneda H, Tanizaki J, Sakai K, Togashi Y, Terashima M, De Velasco MA, Fujita Y, Banno E, Nakamura Y, Takeda M, Ito A, Mitsudomi T, Nakagawa K, Okamoto I, Nishio K. FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. Cancer Sci. 2016 Sep 1. doi: 10.1111/cas.13071. [Epub ahead of print] PubMed PMID: 27581340.

8: Olin JL, Woods JA, Garner SJ. Delayed Presentation of Hepatocellular Liver Injury After Nintedanib Administration. Am J Ther. 2016 Aug 17. [Epub ahead of print] PubMed PMID: 27574930.

9: Espinosa Bosch M, Asensi Diez R, García Agudo S, Clopes Estela A. Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer; GENESIS-SEFH drug evaluation report. Farm Hosp. 2016 Jun 1;40(4):316-27. doi: 10.7399/fh.2016.40.4.10455. PubMed PMID: 27571499.

10: Bonella F, Kreuter M, Hagmeyer L, Neurohr C, Keller C, Kohlhaeufl MJ, Müller-Quernheim J, Milger K, Prasse A; German Nintedanib Compassionate Use Consortium. Insights from the German Compassionate Use Program of Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis. Respiration. 2016;92(2):98-106. doi: 10.1159/000448288. Epub 2016 Aug 20. PubMed PMID: 27544537.

11: Gann CN, Morsli N, Chen X, Barrueco J. Response to 'Dai W et al. Am J Cancer Res 2015;5(10):3270-3275' from the makers of nintedanib. Am J Cancer Res. 2016 Jul 1;6(7):1547-8. eCollection 2016. PubMed PMID: 27508096; PubMed Central PMCID: PMC4969403.

12: Slobbe P, Poot AJ, Haumann R, Schuit RC, Windhorst AD, van Dongen GA. Two anti-angiogenic TKI-PET tracers, [(11)C]axitinib and [(11)C]nintedanib: Radiosynthesis, in vivo metabolism and initial biodistribution studies in rodents. Nucl Med Biol. 2016 Oct;43(10):612-24. doi: 10.1016/j.nucmedbio.2016.07.003. Epub 2016 Jul 14. PubMed PMID: 27497236.

13: Rogliani P, Calzetta L, Cavalli F, Matera MG, Cazzola M. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Pulm Pharmacol Ther. 2016 Oct;40:95-103. doi: 10.1016/j.pupt.2016.07.009. Epub 2016 Jul 29. PubMed PMID: 27481628.

14: Taniguchi H, Xu Z, Azuma A, Inoue Y, Li H, Fujimoto T, Bailes Z, Schlenker-Herceg R, Kim DS. Subgroup analysis of Asian patients in the INPULSIS® trials of nintedanib in idiopathic pulmonary fibrosis. Respirology. 2016 Jul 11. doi: 10.1111/resp.12852. [Epub ahead of print] PubMed PMID: 27399197.

15: Lobo P. Nintedanib data challenge IPF guidelines. Lancet Respir Med. 2016 Aug;4(8):610. doi: 10.1016/S2213-2600(16)30196-5. Epub 2016 Jul 4. PubMed PMID: 27388655.

16: Wuyts WA, Kolb M, Stowasser S, Stansen W, Huggins JT, Raghu G. First Data on Efficacy and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis and Forced Vital Capacity of ≤50 % of Predicted Value. Lung. 2016 Oct;194(5):739-43. doi: 10.1007/s00408-016-9912-1. Epub 2016 Jul 4. PubMed PMID: 27377558.

17: Englinger B, Lötsch D, Pirker C, Mohr T, van Schoonhoven S, Boidol B, Lardeau CH, Spitzwieser M, Szabó P, Heffeter P, Lang I, Cichna-Markl M, Grasl-Kraupp B, Marian B, Grusch M, Kubicek S, Szakács G, Berger W. Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression. Oncotarget. 2016 Jun 29. doi: 10.18632/oncotarget.10324. [Epub ahead of print] PubMed PMID: 27367030.

18: Ryerson CJ, Camp PG, Eves ND, Schaeffer M, Syed N, Dhillon S, Jensen D, Maltais F, O'Donnell DE, Raghavan N, Roman M, Stickland MK, Assayag D, Bourbeau J, Dion G, Fell CD, Hambly N, Johannson KA, Kalluri M, Khalil N, Kolb M, Manganas H, Morán-Mendoza O, Provencher S, Ramesh W, Rolf JD, Wilcox PG, Guenette JA. High Oxygen Delivery to Preserve Exercise Capacity in Patients with Idiopathic Pulmonary Fibrosis Treated with Nintedanib. Methodology of the HOPE-IPF Study. Ann Am Thorac Soc. 2016 Sep;13(9):1640-7. doi: 10.1513/AnnalsATS.201604-267OC. PubMed PMID: 27348402.

19: Nintedanib. Aust Prescr. 2016 Apr;39(2):62-3. doi: 10.18773/austprescr.2016.031. Epub 2016 Feb 22. Review. PubMed PMID: 27340326; PubMed Central PMCID: PMC4917623.

20: Raghu G, Wells AU, Nicholson AG, Richeldi L, Flaherty KR, Le Maulf F, Stowasser S, Schlenker-Herceg R, Hansell DM. Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria. Am J Respir Crit Care Med. 2016 Jun 22. [Epub ahead of print] PubMed PMID: 27331880.

Nintedanib

200.0mg / USD 150.0


Additional Information

Related: CAS#
656247-18-6 (Nintedanib esylate)
656247-17-5 (Nintedanib free base)
928326-83-4 (previously assigned to Nintedanib free base)