Carfilzomib

Base Information

• Chemical Name: Carfilzomib
• CAS No.: 868540-17-4
• Molecular Formula: C₄₀H₅₇N₅O₇
• Molecular Weight: 719.922
• Hs Code.: 29337900
• European Community (EC) Number: 692-054-2
• UNII: 72X6E3J5AR
• ChEMBL ID: CHEMBL451887
• DSSTox Substance ID: DTXSID4048690
• Metabolomics Workbench ID: 63800
• NCI Thesaurus Code: C52196
• Nikkaji Number: J2.711.864J
• Pharos Ligand ID: G55PC23JUAMK
• RXCUI: 1302966
• Wikidata: Q15366934
• Wikipedia: Carfilzomib
• Mol file: 868540-17-4.mol

Synonyms:(2S)-N-((1S)-1-benzyl-2-(((1S)-3-methyl-1-(((2R)-2-methyloxiran-2-yl)carbonyl)butyl)amino)-2-oxoethyl)-4-methyl-2-(((2S)-2-((morpholin-4-ylacetyl)amino)-4-phenylbutanoyl)amino)pentanamide;carfilzomib;Kyprolis;PR-171;PR171

Chemical Property of Carfilzomib

Chemical Property:

• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.551
• Boiling Point: 975.627 °C at 760 mmHg
• PKA: 13.17±0.46(Predicted)
• Flash Point: 543.84 °C
• PSA: 158.47000
• Density: 1.162g/cm³
• LogP: 4.08500
• Storage Temp.: -20°
• Solubility.: Soluble in DMSO (up to 80 mg/ml) or in Ethanol (up to 25 mg/ml).
• XLogP3: 4.7
• Hydrogen Bond Donor Count: 4
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 20
• Exact Mass: 719.42579917
• Heavy Atom Count: 52
• Complexity: 1180

Purity/Quality:

99% ,99.9%, ^*data from raw suppliers

Carfilzomib ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CC(C)CC(C(=O)C1(CO1)C)NC(=O)C(CC2=CC=CC=C2)NC(=O)C(CC(C)C)NC(=O)C(CCC3=CC=CC=C3)NC(=O)CN4CCOCC4
• Isomeric SMILES: CC(C)C[C@@H](C(=O)[C@]1(CO1)C)NC(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC3=CC=CC=C3)NC(=O)CN4CCOCC4
• Recent ClinicalTrials: A Clinical Trial of Four Medicines (Elranatamab Plus Carfilzomib and Dexamethasone or Maplirpacept) in People With Relapsed Refractory Multiple Myeloma
• Recent EU Clinical Trials: Daratumumab in combination with Carfilzomib, Pomalidomide and Dexamethasone (DCPD) in patients with multiple myeloma induced
• Recent NIPH Clinical Trials: A study to investigate subcutaneous isatuximab in combination with carfilzomib and dexamethasone in adult participants with relapsed and/or refractory multiple myeloma
• 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).
• 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 (IC50s 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. The synthesis of carfilzomib is reported in the patent literature and a route to the intermediate epoxy ketone from a Boc-leucine-derived α,β-unsaturated ketone is also described.
• Uses: Carfilzomib is a second-generation proteasome inhibitor that is used as a treatment in relapsed and refractory 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.
• Drug interactions: Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.

Technology Process of Carfilzomib

There total 51 articles about Carfilzomib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.0%

morpholine (110-91-8,99108-56-2) + (S)-2-((S)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)pentanamide → carfilzomib (868540-17-4)

Guidance literature:

With potassium iodide; In tetrahydrofuran; at 20 ℃; for 12h; Inert atmosphere;

DOI:10.1021/jacs.1c04614 DOI:10.1039/d1gc03498g

Reference yield: 88.0%

(S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenyipropanoic acid (868540-16-3) + C9H17NO2*C4HF7O2 → carfilzomib (868540-17-4)

Guidance literature:

With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; diethylamine; In N,N-dimethyl-formamide; at -5 ℃; for 1.5h;

Reference yield: 86.0%

(S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenyipropanoic acid (868540-16-3) + C9H17NO2*C3HF5O2 → carfilzomib (868540-17-4)

Guidance literature:

With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; diethylamine; In N,N-dimethyl-formamide; at -5 ℃; for 1.5h; Temperature; Reagent/catalyst;

upstream raw materials:

(S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenyipropanoic acid

(2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiran-2-yl]pentan-1-one

dichloromethane

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetic acid salt

Refernces

• 1、 Liu, Tao,Zhang, Xue,Peng, Zejun,Zhao, Junfeng. "Water-removable ynamide coupling reagent for racemization-free syntheses of peptides, amides, and esters". . p. 9916 - 9921. Retrieved 2021/12/24.
• 2、 -. "PROCESSES FOR THE PREPARATION OF CARFILZOMIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF". . . Retrieved 2019/09/30.