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Ibrutinib

CAS No.
936563-96-1
Chemical Name:
Ibrutinib
Synonyms
Lbrutinib;1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one;PCI-32765;Ibrutinib (PCI-32765);IBRUTINIB (PCI-32765);PCI32765;1-{3-[4-AMino-3-(4-phenoxy-phenyl)-pyrazolo[3,4-d]pyriMidin-1-yl]-piperidin-1-yl}-propenone;(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-;(R)-1-(3-(4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl)piperidin-1-yl)prop-2-en-1-one;CS-188;Ibutinib
CBNumber:
CB12515873
Molecular Formula:
C25H24N6O2
Molecular Weight:
440.5
MDL Number:
MFCD20261150
MOL File:
936563-96-1.mol
MSDS File:
SDS
Last updated:2025-01-22 16:43:48

Ibrutinib Properties

Melting point 153-158°C
Boiling point 715.0±60.0 °C(Predicted)
Density 1.34
storage temp. -20°C
solubility Soluble in DMSO ( up to at least 25 mg/ml)
form solid
pka 4.09±0.30(Predicted)
color White or off-white
Stability Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChIKey XYFPWWZEPKGCCK-GOSISDBHSA-N
SMILES C(N1CCC[C@@H](N2C3C(C(C4=CC=C(OC5=CC=CC=C5)C=C4)=N2)=C(N)N=CN=3)C1)(=O)C=C
CAS DataBase Reference 936563-96-1
FDA UNII
NCI Drug Dictionary
ATC code

Pharmacokinetic data

Protein binding 97.3%
Excreted unchanged in urine 0 (<10 as metabolites)
Volume of distribution 10 000 Litres
Biological half-life 4-13 / Unchanged

SAFETY

Risk and Safety Statements

Ibrutinib price More Price(42)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Cayman Chemical 16274 Ibrutinib ≥98% 936563-96-1 1mg $36 2024-06-20 Buy
Cayman Chemical 16274 Ibrutinib ≥98% 936563-96-1 5mg $105 2024-06-20 Buy
Cayman Chemical 16274 Ibrutinib ≥98% 936563-96-1 10mg $174 2024-06-20 Buy
Cayman Chemical 16274 Ibrutinib ≥98% 936563-96-1 50mg $777 2024-06-20 Buy
Tocris 6813 Ibrutinib ≥98%(HPLC) 936563-96-1 10 $150 2022-12-16 Buy
Product number Packaging Price Buy
16274 1mg $36 Buy
16274 5mg $105 Buy
16274 10mg $174 Buy
16274 50mg $777 Buy
6813 10 $150 Buy

Ibrutinib Chemical Properties,Uses,Production

Bruton tyrosine kinase (BTK) inhibitor

Ibrutinib[936563-96-1] is a Bruton's tyrosine kinase (BTK) inhibitor used for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). MCL and CLL are both B-cell non-Hodgkin lymphomas, characterized by treatment resistance and high rate of relapse. Conventional chemotherapy and immunotherapy lack specificity and often result in grade 3 or 4 adverse reactions. Ibrutinib selectively binds to BTK, an essential component for B lymphocyte formation, differentiation, signaling, and survival, irreversibly inhibiting its activity. It effectively inhibits tumor cell proliferation and survival. Additionally, it is rapidly absorbed after oral administration, reaching peak blood concentration in 1-2 hours, and adverse reactions are usually grade 1 or 2. Ibrutinib will become a new treatment option for CLL and MCL.
On November 13, 2013, the US Food and Drug Administration (FDA) accelerated the approval of Imbruvica (generic name: Ibrutinib) manufactured by Pharmacyclics and Johnson & Johnson for the treatment of a rare aggressive blood cancer called mantle cell lymphoma (MCL). Ibrutinib is an orally available Bruton's tyrosine kinase (BTK) inhibitor, which is a first-in-class innovative drug. It was granted breakthrough therapy designation by the FDA in February 2013 and approved for the treatment of MCL and chronic lymphocytic leukemia (CLL) on November 13, 2013, and February 12, 2014, respectively. This drug selectively and irreversibly inhibits BTK by covalently binding to the active site cysteine residue (Cys-481) of the target protein Btk, effectively preventing the tumor from migrating from B cells to lymphoid tissues that are conducive to tumor growth.
Information was collated by Xiaonan editor of Chemicalbook.

Research and development process

Ibrutinib was developed by American Celera Genentech (Celera Genomics) that was well known because it was the first one drawn "human genome". Pan Zhengying (now Beijing University Shenzhen Graduate School Distinguished Fellow) as the first author of this research and published the process of Ibrutinib in 2007 (ChemMedChem 2 (1): 58-61). But Celera had transferred the development rights to Pharmacyclics Company of California due to funding and resources. Although Pharmacyclics Company was in a very difficult stage, only $ 0.64 for the stock, facing delisting and bankruptcy in that time, company's management has managed to raise funds, spent only $ 2 million to down payment, 100 million shares and future sales royalty and milestone payment of royalties more to get Ibrutinib. In 2011, Johnson & Johnson subsidiary Janssen pay $ 150 million upfront payment in order to get the right to cooperate with Pharmacyclics. Once the new drugs in clinical trials and approved to listing, Pharmacyclics company will get $ 975 million in total revenue, and they will share the sales.When the deal was announced, Pharmacyclics stock is only $ 12. Market value was only several hundred million dollars. However, the stock is already $ 123, $ 9.05 billion value now.

Mechanism

Signaling pathway of B cell antigen receptor (BCR) is a key driver of tumor growth and spread. BTK as an indispensable participant for BCR signal peptide, it is very important for formation, differentiation, messaging and survival of B lymphocyte. BTK is an identifiable signal peptide molecules of BCR channel. When the signal peptide molecules across the B lymphocyte surface receptors, required channel is activated for transportation, chemotaxis and adhesion, which provide a convenience to be B-cell malignancies.
Ibrutinib is a small molecule can selectively and covalently bound to a cysteine residue (Cys-481) BTK active site, and irreversibly inhibit BTK activity, thereby inhibiting BCR activated signaling pathway, which could effectively prevent the tumor from B cells to lymphoid tissues where suitable for tumor growth, to reduce B cell proliferation and induce apoptosis of malignant cells, which play a role in the treatment of CLL and MCL. Non-clinical studies have shown that Ibrutinib can inhibit malignant B lymphocyte proliferation and survival.

Metabolism and Elimination

Ibrutinib primarily metabolized by the cytochrome P450 (CYP3A and a small part of the CYP2D6) and produce a variety of metabolites after metabolism. The metabolite (PCI-45227) is a kind of dihydrodiol substance which is an activity of inhibiting BTK.Compared with Ibrutinib, PCI-45227 has much stronger inhibition on BTK, which is about 15 times stronger. At steady state, the average rate of metabolism of PCI-45227 is around 1~2.8.
Apparent clearance (CL/F) of Ibrutinibis is approximately 1 000 L/h, the half-life (t1/2) is 4~6 h. Ibrutinib mainly be metabolites in the body, excrete with the feces. To healthy subjects by oral radioactive 14C-labeled Ibrutinib, found that nearly 90% of the radiation were eliminated in 168 h, most (about 80%) of them were excreted with the feces, and nearly 10% were excreted in the urine, about 1 % be prototypes were excreted with the feces.
Elimination of Ibrutinib will not make a difference in age (37 to 84 years) and gender, but systemic exposure of patients with moderate hepatic injury will be 6 times higher than in healthy subjects.

Patents

Foreign patents: WO 2008039218 (compound); WO 2013003629 (purposes)
US Patent Number: 7,514,444, 7,718,662, patents is valid: December 2026
Domestic patent: CN101610676A, CN101610676B, CN101805341A, CN101805341B, CN102746305A, CN102887900A

Description

Ibrutinib (CAS: 936563-96-1) is a first-in-class,potent, orally administered covalently-binding inhibitor of BTK. In November 2013, the US FDA approved ibrutinib (also referred to as PCI-32765), for the treatment of patients with mantle cell lymphoma (MCL) who had received at least one prior therapy. Ibrutinib is a potent inhibitor of BTK that binds covalently to Cys-481 in the active site of BTK, resulting in inhibition of kinase activity. Ibrutinib does have significant activity against 19 other kinases, including seven with a cognate cysteine residue. These include BLK, BMX, ITK, TEC, EGFR, ERBB2, and JAK3.

Originator

Celera/Pharmacyclics (United States)

Uses

Ibrutinib is a highly selective Bruton’s tyrosine kinase (Btk) irreversible inhibitor.

Indications

Ibrutinib is a non-receptor Bruton's tyrosine kinase inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia(CLL), mantle cell lymphoma (MCL) and WaldenstrÖm's Macroglobulinemia (WM).

Definition

ChEBI: Ibrutinib is a member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrazolopyrimidine, an aromatic amine, an aromatic ether, a member of acrylamides, a N-acylpiperidine and a tertiary carboxamide.

brand name

Imbruvica

Synthesis

Condensation of commercially available 4-phenoxybenzoyl chloride (88) with malononitrile followed by acidic quench and O-methylation with dimethyl sulfate furnished vinyl dinitrile 89 in 84% yield over the three-step sequence. Next, treatment with hydrazine hydrate in refluxing ethanol secured aminopyrazole 90 and this was followed by treatment with neat formamide at elevated temperature to furnish pyrimidopyrazole 91 in excellent conversion. Selective alkylation of the pyrazole nitrogen with commercially- available (S)-piperidinyl tosylate (92) proceeded in 32% yield. Finally, liberation of the amide followed by pH adjustment and amide bond formation with acrolyl chloride furnished ibrutinib (XI) in 50% over the three-step sequence.

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Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: concentration possibly increased by amiodarone and dronedarone - avoid or reduce dose of ibrutinib.
Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin, erythromycin and telithromycin - avoid or reduce dose of ibrutinib; concentration reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital and phenytoin - avoid.
Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole and voriconazole - avoid or reduce dose of ibrutinib
. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Antivirals: concentration possibly increased by atazanavir, darunavir, fosamprenavir, indinavir, ritonavir and saquinavir - avoid or reduce dose of ibrutinib.
Aprepitant: concentration possibly increased - avoid or reduce dose of ibrutinib.
Calcium channel blockers: concentration possibly increased by diltiazem or verapamil - avoid or reduce dose of ibrutinib.
Cobicistat: concentration possibly increased, avoid or reduce dose of ibrutinib.
Cytotoxics: concentration possibly increased by crizotinib - avoid or reduce dose of ibrutinib; concentration possibly increased by imatinib - reduce dose of ibrutinib.
Grapefruit juice and Seville oranges: avoid.

Metabolism

Ibrutinib is metabolised primarily by CYP3A4 to produce a dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Involvement of CYP2D6 in the metabolism of ibrutinib appears to be minimal.
After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the faeces and <10% in the urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in faeces and none in urine.

storage

+4°C

Mode of action

Ibrutinib is the second oral agent approved for the treatment of MCL. It works by irreversibly inhibiting Bruton’s tyrosine kinase (Btk) leading to the inhibition of B-cell receptor signaling and resulting in the reduction of malignant B-cell proliferation and induction of cell death. Btk plays an important role in the differentiation, development, proliferation, and survival of B cells via activation of cell-cycle regulators and regulating the expression of pro- and antiapoptotic proteins. Aberrant Btk activity results in a variety of B-cell malignancies including MCL. Ibrutinib inhibits Btk by irreversibly binding to cysteine-481 in the active site thereby inhibiting phosphorylation of tyrosine-223 and affecting downstream B-cell signaling pathways.

References

1) Honigberg?et al.?(2010),?The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy;?Proc. Natl. Acad. Sci. USA?107?13075 DOI:
2) Ponader?et al.?(2012),?The Bruton tyrosine kinase Inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo;?Blood?119?1182
DOI:
3) De Rooij?et al.?(2012),?The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia;?Blood?119?2590
DOI:
4) Pavlasoca?et al.?(2016),?Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis;?Blood?128?1609 DOI:
5) Sagiv-Barfi?et al.?(2015),?Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK; Proc. Natl. Acad. Sci. USA?112?E966 DOI:
6) Weber?et al.?(2017),?Bruton's Tyrosine Kinase: An Emerging Key Player in Innate Immunity,?Front. Immunol.?8?1454 DOI:

Ibrutinib Preparation Products And Raw materials

Raw materials

Preparation Products

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Capot Chemical Co.,Ltd.
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936563-96-1
US $1.00 / g 1g 99% 100kg Dorne Chemical Technology co. LTD
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936563-96-1
US $0.00 / kg 1kg 0.99 10T Shandong Hanjiang Chemical Co., Ltd
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936563-96-1
US $3.90-3.90 / g 10g 99.99%HPLC.USP42——Powder、Oil、Pills、Capsules、Tablets,Customiz 10kg Wuhan Biocar Pharmacy Co., Ltd.
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Ibrutinib Spectrum

According to Lu imatinib 2-Propen-1-one, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]- PCI-32765 (Ibrutinib) IBRUTINIB 1-[(3R)-3-[4-AMino-3-(4-phenoxyphenyl)pyrazolo[3, 4-d]pyriMidin-1-yl]piperidin-1-yl]prop-2-en-1-one 1-{3-[4-Amino-3-(4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-but-3-en-1-one 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one Ibrutinib (PCI32765) PCI-32765 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one Ibrutinib, >=98% Factory supply high quality Ibrutinib Cas 936563-96-1 with best price and fast delivery CS-188 Ibrutinib (API) N6-(2-Carboxyethyl)  1-[3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3, 4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one (Ibrutinib) According to lu for Ibrutinib ISO 9001:2015 REACH Ibrutinib acetate salt 1-[3-[4-Amino-3-(4-phenoxyphenyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinyl]-2-propen-1-one 1-((3r)-3-(4-amino-3-(4-phenoxyphenyl)-1h-pyrazolo(3,4-d)pyr... PCI-32765 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one IBRUTINIB (PCI-32765);PCI32765 (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2- (R)-1-(3-(4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl)piperidin-1-yl)prop-2-en-1-one Ibrutinib (PCI-32765) 1-{3-[4-AMino-3-(4-phenoxy-phenyl)-pyrazolo[3,4-d]pyriMidin-1-yl]-piperidin-1-yl}-propenone Lbrutinib LITHIUM METASILICATE 10102-24-6 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-2-propen-1-one Ibutinib 1- [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-D] pyrimidin-1-yl] -1-piperidinyl] -2-propenyl-1-one Ibrutinib (Form A) Ibrutinib AP Ibrutinib Crude (R)-1-[3-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one 936563-96-1 996563-96-1 C25H24N6O2 C25H24O2N6 Inhibitor Inhibitors Anticancer API 936563-96-1
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