Nilotinib HCl hydrate

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WARNING: This product is for research use only, not for human or veterinary use.

Description:Nilotinib, also known as AMN-107, is an orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein, resulting in the inhibition of the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs).

Price and Availability

Nilotinib HCl hydrate, purity > 98%, is in stock. The same day shipping out after order is received. Note: the estimated shipping out time for order > 50g may be 2 weeks.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 100673Name: Nilotinib HCl hydrateCAS#: 923288-90-8 (HCl hydrate)Chemical Formula: C28H25ClF3N7O2Exact Mass: 529.1838Molecular Weight: 584.0Elemental Analysis: C, 57.59; H, 4.32; Cl, 6.07; F, 9.76; N, 16.79; O, 5.48

Related CAS #:923288-90-8 (HCl hydrate)923288-95-3(HCl)641571-10-0 (free base)

Synonym:AMN 107; AMN107; AMN-107; Nilotinib; US brand name: Tasigna. Nilotinib HCl hydrate.

IUPAC/Chemical Name:4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate

InChi Key:YCBPQSYLYYBPDW-UHFFFAOYSA-N

InChi Code:InChI=1S/C28H22F3N7O.ClH.H2O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38;;/h3-16H,1-2H3,(H,35,39)(H,33,36,37);1H;1H2

SMILES Code:O=C(NC1=CC(C(F)(F)F)=CC(N2C=C(C)N=C2)=C1)C3=CC=C(C)C(NC4=NC=CC(C5=CC=CN=C5)=N4)=C3.[H]Cl.[H]O[H]

Technical Data

Additional Information

 Nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib, also known by its clinical code AMN107, has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study 92% of patients (already resistant or unresponsive to Gleevec) achieved a normal white blood cell counts after five months of treatment. The drug carries a black box warning for possible heart complications. Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors. Nilotinib drug substance, a monohydrate mono-hydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 565.98. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4. The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate.  Tasigna (nilotinib) capsules, for oral use, contain 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and polyoxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), and titanium dioxide. Nilotinib is an inhibitor of the Bcr-Abl kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM), c-Kit (210 nM), CSR-1R (125-250 nM) and DDR (3.7 nM).  

References

1: Breccia M, Arboscello E, Bellodi A, Colafigli G, Molica M, Bergamaschi M, Massaro F, Quattrocchi L, Sarocchi M, Spallarossa P, Alimena G. Proposal for a tailored stratification at baseline and monitoring of cardiovascular effects during follow-up in chronic phase chronic myeloid leukemia patients treated withnilotinib frontline. Crit Rev Oncol Hematol. 2016 Nov;107:190-198. doi: 10.1016/j.critrevonc.2016.10.002. Review. PubMed PMID: 27823647.

2: Fujimi A, Sakamoto H, Kanisawa Y, Minami S, Nagamachi Y, Yamauchi N, Ibata S,Kato J. Pneumatosis intestinalis during chemotherapy with nilotinib in a patientwith chronic myeloid leukemia who tested positive for anti-topoisomerase I antibodies. Clin J Gastroenterol. 2016 Dec;9(6):358-364. Review. PubMed PMID: 27638345.

3: Emole J, Talabi T, Pinilla-Ibarz J. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: role of nilotinib. Biologics. 2016 Feb 26;10:23-31. doi: 10.2147/BTT.S67844. Review. PubMed PMID: 27013862; PubMed Central PMCID: PMC4777272.

4: Sekiguchi Y, Shimada A, Matsuzawa M, Imai H, Wakabayashi M, Sugimoto K, Nakamura N, Sawada T, Arita J, Komatsu N, Noguchi M. Occurrence of Carcinoma of the Pancreas Following Nilotinib Therapy for Chronic Myeloid Leukemia: Report ofa Case with Review of the Literature. Turk J Haematol. 2015 Sep;32(3):257-62. doi: 10.4274/tjh.2013.0322. Review. PubMed PMID: 26376592; PubMed Central PMCID:PMC4563202.

5: Miura M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia. Biol Pharm Bull. 2015;38(5):645-54. doi:10.1248/bpb.b15-00103. Review. PubMed PMID: 25947908.

6: Kaur S, Arora AK, Sekhon JS, Sood N. Nilotinib-induced psoriasis in a patientof chronic myeloid leukemia responding to methotrexate. Indian J Dermatol Venereol Leprol. 2015 Mar-Apr;81(2):216-8. doi: 10.4103/0378-6323.152311. Review. PubMed PMID: 25751356.

7: Weisberg E, Nonami A, Griffin JD. Combination therapy with nilotinib for drug-sensitive and drug-resistant BCR-ABL-positive leukemia and other malignancies. Arch Toxicol. 2014 Dec;88(12):2233-42. doi: 10.1007/s00204-014-1385-5. Review. PubMed PMID: 25331939.

8: Ostendorf BN, le Coutre P, Kim TD, Quintás-Cardama A. Nilotinib. Recent Results Cancer Res. 2014;201:67-80. doi: 10.1007/978-3-642-54490-3_3. Review. PubMed PMID: 24756785.

9: Capuozzo M, Ottaiano A, Nava E, Cascone S, Cinque C, Vercellone A, Scognamiglio C, Palumbo E, Iaffaioli RV. Nilotinib for the Frontline Treatment of Chronic Myeloid Leukemia Carrying the p230 Transcript: Dream or Reality? Front Oncol. 2014 Feb 3;4:17. doi: 10.3389/fonc.2014.00017. Review. PubMed PMID: 24551597; PubMed Central PMCID: PMC3910244.

10: Signorovitch J, Ayyagari R, Reichmann WM, Wu EQ, Chen L. Major molecular response during the first year of dasatinib, imatinib or nilotinib treatment fornewly diagnosed chronic myeloid leukemia: a network meta-analysis. Cancer Treat Rev. 2014 Mar;40(2):285-92. doi: 10.1016/j.ctrv.2013.09.004. Review. PubMed PMID: 24112812.

11: Eadie LN, Hughes TP, White DL. Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib. Clin Pharmacol Ther. 2014 Mar;95(3):294-306. doi: 10.1038/clpt.2013.208. Review. PubMed PMID: 24107928.

12: Kanda T, Ishikawa T, Takahashi T, Nishida T. Nilotinib for treatment of gastrointestinal stromal tumors: out of the equation? Expert Opin Pharmacother. 2013 Sep;14(13):1859-67. doi: 10.1517/14656566.2013.816676. Review. PubMed PMID:23834614.

13: Brazzelli V, Grasso V, Borroni G. Imatinib, dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience. J Eur Acad Dermatol Venereol. 2013 Dec;27(12):1471-80. doi: 10.1111/jdv.12172. Review.PubMed PMID: 23611501.

14: Quintás-Cardama A, Jabbour EJ. Considerations for early switch to nilotinib or dasatinib in patients with chronic myeloid leukemia with inadequate response to first-line imatinib. Leuk Res. 2013 May;37(5):487-95. doi: 10.1016/j.leukres.2013.01.006. Review. PubMed PMID: 23391518.

15: Deadman BJ, Hopkin MD, Baxendale IR, Ley SV. The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib. Org Biomol Chem. 2013 Mar 21;11(11):1766-800. doi: 10.1039/c2ob27003j. Review. PubMed PMID: 23247657.

16: Drucker AM, Wu S, Busam KJ, Berman E, Amitay-Laish I, Lacouture ME. Rash with the multitargeted kinase inhibitors nilotinib and dasatinib: meta-analysis and clinical characterization. Eur J Haematol. 2013 Feb;90(2):142-50. doi: 10.1111/ejh.12052. Review. PubMed PMID: 23240881.

17: Pavey T, Hoyle M, Ciani O, Crathorne L, Jones-Hughes T, Cooper C, Osipenko L, Venkatachalam M, Rudin C, Ukoumunne O, Garside R, Anderson R. Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses. Health Technol Assess. 2012;16(42):iii-iv, 1-277. doi: 10.3310/hta16420. Review. PubMed PMID: 23134589.

18: Loveman E, Cooper K, Bryant J, Colquitt JL, Frampton GK, Clegg A. Dasatinib,high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronicmyeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(23):iii-xiii, 1-137. doi: 10.3310/hta16230. Review. PubMed PMID:22564553; PubMed Central PMCID: PMC4781455.

19: Rogers G, Hoyle M, Thompson Coon J, Moxham T, Liu Z, Pitt M, Stein K. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(22):1-410. doi: 10.3310/hta16220. Review. PubMed PMID: 22551803; PubMed Central PMCID: PMC4781389.

20: Tran A, Tawbi HA. A potential role for nilotinib in KIT-mutated melanoma. Expert Opin Investig Drugs. 2012 Jun;21(6):861-9. doi: 10.1517/13543784.2012.679341. Review. PubMed PMID: 22500535.