Carfilzomib

Carfilzomib Properties

Melting point	204 - 208°C
Boiling point	975.6±65.0 °C(Predicted)
Density	1.161
Flash point	543.8℃
storage temp.	-20°
solubility	Soluble in DMSO (up to 80 mg/ml) or in Ethanol (up to 25 mg/ml).
form	solid
pka	13.17±0.46(Predicted)
color	White
Stability	Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 week.
InChIKey	BLMPQMFVWMYDKT-KWQOZBPPNA-N
SMILES	C([C@@]1(OC1)C)(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CN1CCOCC1)CCC1C=CC=CC=1)CC1C=CC=CC=1 \|&1:1,6,14,18,26,r\|
CAS DataBase Reference	868540-17-4
FDA UNII	72X6E3J5AR
NCI Dictionary of Cancer Terms	carfilzomib; carfilzomib
NCI Drug Dictionary	carfilzomib
ATC code	L01XG02

Pharmacokinetic data

Protein binding	97%
Excreted unchanged in urine	25 (as metabolites)
Volume of distribution	28 Litres
Biological half-life	<1 / Unchanged

SAFETY

Risk and Safety Statements

Symbol(GHS)	GHS07
Signal word	Warning
Hazard statements	H302-H315-H319-H335
Precautionary statements	P261-P305+P351+P338
HS Code	29337900

Carfilzomib price More Price(45)

Manufacturer	Product number	Product description	CAS number	Packaging	Price	Updated	Buy
Cayman Chemical	17554	Carfilzomib ≥98%	868540-17-4	5mg	$32	2024-03-01	Buy
Cayman Chemical	17554	Carfilzomib ≥98%	868540-17-4	25mg	$78	2024-03-01	Buy
Cayman Chemical	17554	Carfilzomib ≥98%	868540-17-4	1mg	$35	2021-12-16	Buy
Cayman Chemical	17554	Carfilzomib ≥98%	868540-17-4	10mg	$48	2024-03-01	Buy
Cayman Chemical	17554	Carfilzomib ≥98%	868540-17-4	50mg	$109	2024-03-01	Buy

Product number	Packaging	Price	Buy
17554	5mg	$32	Buy
17554	25mg	$78	Buy
17554	1mg	$35	Buy
17554	10mg	$48	Buy
17554	50mg	$109	Buy

Carfilzomib Chemical Properties,Uses,Production

description

Carfilzomib is an irreversible proteasome inhibitor and antineoplastic agent.The mechanism of action of carfilzomib is as a Proteasome Inhibitor, Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S catalytic core subunit of the proteasome, a protease complex responsible for degrading a large variety of cellular proteins. Inhibition of proteasome-mediated proteolysis results in an accumulation of polyubiquinated proteins, which may lead to cell cycle arrest, induction of apoptosis, and inhibition of tumor growth.
Carfilzomib is used in treatment of refractory multiple myeloma. Carfilzomib is associated with a low rate of serum enzyme elevations during treatment and has been implicated to rare instances of clinically apparent, acute liver injury some of which have been fatal.
Carfilzomib is a second-generation, irreversible, peptide epoxyketone class proteasome inhibitor that targets the chymotrypsin-like β5 subunit of the constitutive 20S proteasome (IC50 = 5.2 nM) and the β5i subunit of the immunoproteasome 20Si (LMP7; IC50 = 14 nM) with minimal cross reactivity to other proteases. It can induce cell cycle arrest and apoptosis in human cancer cell lines including multiple myeloma, lymphoma, and various solid tumors (IC50s = 2.4-20 nM).
Carfilzomib

Mechanism

Carfilzomib is a tetrapeptide-based epoxy-proteasome inhibitor that irreversibly binds to the 20S proteasome containing the threonine N-terminal active site and the in vivo proteolysis core particle of 26S proteasome. In animal, carfilzomib has antiproliferative and apoptosis activity in vitro in solid and hematological granulocytes. In animals, carfilzomib inhibits proteasome activity in blood and tissue and delays tumor growth in multiple myeloma, hematological and solid tumor models.

Side effects

The most common adverse events observed in clinical trials (incidence ≥30%) were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea and fever; the most common serious adverse events (overall incidence 45%) include pneumonia, acute renal failure, fever and congestive heart failure.

Efficacy and Safety

To assess the safety and efficacy of the drug, one study included 266 patients who had received at least two prior therapies, including bortezomib and thalidomide. It was assessed of the complete or partial disappearance of the tumor in the treated patient (overall response rate). The overall response rate was 23% and the median response time was 7.8 months.
Common adverse effects of carfilzomib were observed in more than 30% of the subjects include fatigue, low blood cell counts and platelet counts, dyspnea, diarrhea and fever. Severe adverse reactions include heart failure and dyspnea. Upon the occurrence of serious adverse reactions, the patient should be closely monitored and stop the drug treatment.
Information regarding the pharmacological effects, indications, mechanism of action, indications and side effects of Carfilzomib, a drug for treating multiple myeloma (MM), were compiled and edited by Xiao Nan of ChemicalBook.

Description

In July 2012, the US FDA approved carfilzomib (also referred to as PR-171) for the treatment of patients with multiple myeloma (MM) who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression within 60 days of completion of the last therapy. Carfilzomib binds to and irreversibly inhibits the chymotrypsin-like protease activity of the constitutive proteosome (β5) and immunoproteosome (β5i) via its epoxyketone pharmacophore. Proteosome inhibition results in the accumulation of polyubiquitinated proteins and induction of apoptosis through activation of both the intrinsic and extrinsic caspase pathways. Carfilzomib inhibits chymotrypsin activity with an IC₅₀ of 6 nM and is less potent an inhibitor of trypsin and caspase (IC_50s of 3600 and 2400 nM, respectively). Cell cycle arrest and apoptosis are seen in a variety of hematologic and solid tumor cell lines (e.g.,MM, acutemyeloid leukemia (AML), pancreatic cancer, lung cancer) treated with carfilzomib.

Chemical Properties

White Solid

Originator

Proteolix Inc. (United States)

Uses

Carfilzomib is a second-generation proteasome inhibitor that is used as a treatment in relapsed and refractory multiple myeloma.

Definition

ChEBI: Carfilzomib is a synthetic tetrapeptide consisting of morpholin-4-acetyl, L-2-amino-4-phenylbutanoyl, L-leucyl and L-phenylalanyl residues joined in sequence with the C-terminus connected to the amino group of (2<element S)-2-amino-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-1-one via an amide linkage. Used for the treatment of patients with multiple myeloma.

Clinical Use

Carfilzomib is an irreversible inhibitor of the chymotrypsin-like protease in the proteasome and was approved in the U.S. for the treatment of multiple myeloma. Carfilzomib was discovered by Proteolix which was later acquired by Onyx Therapeutics who completed the development of this drug. Carfilzomib is also undergoing clinical evaluation for additional oncology indications such as relapsed solid tumors, lymphoma, prolymphocytic leukemia, acute myeloid leukemia and acute lymphocytic leukemia.

Synthesis

Carfilzomib is an analog of the natural product epoxomicin which was first synthesized in the laboratories of Professor Crews at Yale University. Subsequent development of the SAR led to the discovery of YU-101 in which 3 of the amino acids of this pentapeptide were modified to improve the potency of the molecule. After licensing the molecule to Proteolix, the introduction of the morpholino group was found to improve the solubility of the drug while maintaining efficient interaction with the target. The most scalable route to carfilzomib closely resembles the original route developed toward epoximicin and is described herein.
The synthesis was initiated with the amide coupling of phenyl alanine methyl ester (53) and N-Boc leucine (54) using standard coupling reagents to afford dipeptide 55 in high yield the Scheme below. Acidic removal of the amine protecting group followed by a second amide coupling reaction with N-Boc homophenyl alanine provided tripeptide 56 in 85% yield for the two steps. Acidic removal of the amine protecting group followed by acylation with chloroacetyl chloride provided |?-chloro amide 57 in 67% yield. Reaction of 57 with morpholine in the presence of catalytic amounts of potassium iodide followed by saponification of the methyl ester with lithium hydroxide provided acid 58 in 87% yield for the two steps. Amide coupling between acid 58 and keto-epoxyamine 59 (whose preparation is described in the scheme below) using HOBT as the coupling reagent followed by recrystallization of the resulting product ultimately gave carfilzomib (IX) in 75% yield.
Synthesis_868540-17-4

Keto-epoxyamine 59 was prepared from N-Boc leucine (54) as described in the Scheme below. Reaction of 54 with isobutyl chloroformate followed by N,O-dimethylhydroxylamine provided Weinreb amide 60 in 94% yield. Grignard addition of isopropenylmagnesium bromide 60 provided enone 62 in 81% yield. Epoxidation of 62 with calcium hypochlorite provided a mixture of epoxides giving 41% yield of the desired isomer (presumably isolated by chromatography), and subsequent treatment with TFA liberated the amine, providing the TFA salt of ketoepoxy amine 59 in 92% yield.
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target

Proteasome

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.

Metabolism

Carfilzomib was rapidly and extensively metabolised by mainly peptidase cleavage and epoxide hydrolysis. Cytochrome P450 mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.

storage

Store at -20°C

References

1) Bennett and Kirk (2008)?Development of proteasome inhibitors in oncology and autoimmune diseases; Curr. Opin. Drug Disc. Dev.?11?616 2) Hanada?et al.?(1992),?Epoxomicin, a new antitumor agent of microbial origin; J. Antibiot. (Tokyo),?45?174 3) Demo?et al. (2007)?Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome; Cancer Res.?67?6383 4) Kuhn?et al. (2007),?Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma; Blood,?110?328

Carfilzomib Preparation Products And Raw materials

Raw materials

Preparation Products

Carfilzomib Suppliers

Global( 358)Suppliers

Supplier	Tel	Email	Country	ProdList	Advantage
Protheragen-ING	+16313385890	info@protheragen-ing.com	United States	3868	58
Shaanxi Haibo Biotechnology Co., Ltd	+undefined18602966907	qinhe02@xaltbio.com	China	997	58
Hangzhou Hyper Chemicals Limited	+86-0086-57187702781 +8613675893055	info@hyper-chem.com	China	295	58
Henan Tianfu Chemical Co.,Ltd.	+86-0371-55170693 +86-19937530512	info@tianfuchem.com	China	21634	55
Chembon Pharmaceutical Co., Ltd.	+86-28-8425-2981		CHINA	722	55
Hangzhou FandaChem Co.,Ltd.	+8615858145714	FandaChem@Gmail.com	China	9087	55
ATK CHEMICAL COMPANY LIMITED	+undefined-21-51877795	ivan@atkchemical.com	China	32957	60
Lianyungang happen teng technology co., LTD	15950718863	wang666xt@163.com	CHINA	295	58
career henan chemical co	+86-0371-86658258 +8613203830695	sales@coreychem.com	China	29880	58
Biochempartner	0086-13720134139	candy@biochempartner.com	CHINA	965	58

Supplier	Advantage
Protheragen-ING	58
Shaanxi Haibo Biotechnology Co., Ltd	58
Hangzhou Hyper Chemicals Limited	58
Henan Tianfu Chemical Co.,Ltd.	55
Chembon Pharmaceutical Co., Ltd.	55
Hangzhou FandaChem Co.,Ltd.	55
ATK CHEMICAL COMPANY LIMITED	60
Lianyungang happen teng technology co., LTD	58
career henan chemical co	58
Biochempartner	58

View Lastest Price from Carfilzomib manufacturers

Update time	Product	Price	Min. Order	Purity	Supply Ability	Manufacturer
2024-12-23	Carfilzomib 868540-17-4	US $0.00 / Kg/Bag	2Kg/Bag	0.99	20 tons	Sinoway Industrial co., ltd.
2024-12-13	Carfilzomib 868540-17-4	US $0.00-0.00 / g	10g	99%min	10kg	WUHAN FORTUNA CHEMICAL CO., LTD
2024-11-15	Carfilzomib 868540-17-4	US $48.00-97.00 / mg		99.84%	10g	TargetMol Chemicals Inc.

Carfilzomib
868540-17-4
US $0.00 / Kg/Bag
0.99
Sinoway Industrial co., ltd.

Carfilzomib
868540-17-4
US $0.00-0.00 / g
99%min
WUHAN FORTUNA CHEMICAL CO., LTD

Carfilzomib
868540-17-4
US $48.00-97.00 / mg
99.84%
TargetMol Chemicals Inc.

Carfilzomib Spectrum

Carfilzomib(868540-17-4)¹HNMR

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CarfilzoMib salt CarfilzoMib/PR 171 PR 171 PR-171 (CarfilzoMib) (alphaS)-alpha-[(4-Morpholinylacetyl)amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-L-phenylalaninamide Carfilzomib CarfilzoMib, Free Base, >99% (S)-4-Methyl-N-((S)-1-((S)-4-Methyl-1-((R)-2- Methyloxiran-2-yl)-1 -oxopentan-2-ylaMino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-MorpholinoacetaMido)-4-phenylbutanaMido)pentanaMide L-Phenylalaninamide, (αS)-α-[[2-(4-morpholinyl)acetyl]amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyl-2-oxiranyl]carbonyl]butyl]- (alphaS)-alpha-[(4-Morpholinylacetyl)amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-L-phenylalaninamide Carfilzomib(PR171) Carfilzomib (alphaS)-alpha-[(4-Morpholinylacetyl)amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-L-phenylalaninamide Carfilzomib, >=99% (αS)-α-[[2-(4-Morpholinyl)acetyl]amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyl-2-oxiranyl]carbonyl]butyl]-L-phenylalaninamide (S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo N-{(2S)-2-[(Morpholin-4-ylacetyl)aMino]-4-phenylbutanoyl}-L-leucyl-N-{(2S)-4-Methyl-1-[(2R)-2-Methyloxiran-2-yl]-1-oxopentan-2-yl}-L-phenylalaninaMide Carfilzomib API and intermediates Carfilzomib, 99%, irreversible proteasome inhibitor PR171;PR 171 CS-603 Carfilzomib API Carfilzomib (2R,4S)-Diol (7R)-Isomer Carfilzomib (2S,4S)-Diol (7R)-Isomer Carfilzomib (2S,4R)-Diol (7R)-Isomer Carfilzomib (2R,4R)-Diol (7R)-Isomer (S)-4-Methyl-N-[(S)-1-[[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxo-2-pentyl]amino]-1-oxo-3-phenyl-2-propyl]-2-[(S)-2-(2-morpholinoacetamido)-4-phenylbutanamido]pentanamide 7(R)-epi Carfilzomib (2R,4S)-diolQ: What is 7(R)-epi Carfilzomib (2R,4S)-diol Q: What is the CAS Number of 7(R)-epi Carfilzomib (2R,4S)-diol 7(R)-epi Carfilzomib (2S,4R)-diolQ: What is 7(R)-epi Carfilzomib (2S,4R)-diol Q: What is the CAS Number of 7(R)-epi Carfilzomib (2S,4R)-diol L-Phenylalaninamide, (αS)-α-[[2-(4-morpholinyl)acetyl]amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyl-2-oxiranyl]carbonyl]butyl]- (Carfilzomib impurity) (αS)-α-[[2-(4-Morpholinyl)acetyl]amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyl-2-oxiranyl]carbonyl]butyl]-L-phenylalaninamide Carfilzomib（For R & D only） Carfezomil Caffezomib 868540-17-4 86854-17-4 C40H57N5O7 Inhibitors peptides API Inhibitor Pharmaceutical 868540-17-4 Coronavirus