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XL518
- Iupac Name：[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone
- CAS No.: 934660-93-2
- Molecular Weight：531.3100196
- Modify Date.: 2022-11-25 06:18
- Introduction: Cobimetinib, codeveloped byGenentech and Exelixis, was approved in August 2015 inSwitzerland and November 2015 in the U.S. and Europe for thetreatment of unresectable or metastatic BRAFV600 mutationpositivemelanoma when used in combination with vemurafenib. Cobimetinib is a potent, highly selective reversibleinhibitor of mitogen-activated protein kinases (MEK) 1 and2,120 which serves to inhibit phosphorylation of ERK1/2,121disrupting the MAPK pathway which is responsible for cellproliferation, cell survival, and migration.122 Combination ofcobimetinib with vemurafenib, an important BRAF inhibitor,123enables targeting of multiple points on the MAPK pathway,leading to overall enhanced tumor cell apoptosis and responseas compared to stand-alone treatment with vemurafenib.124Specifically, in a representative trial of previously untreatedpatients with BRAFV600 mutation-positive, unresectable, stageIIIc or IV melanoma, combination of these two therapies led toa significantly improved progression-free survival and overallresponse rate versus patients treated only with vemurafenib.
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1. Names and Identifiers
- 1.1 Name
- XL518
- 1.2 Synonyms
(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)Methanone [3,4-Bis(Fluoranyl)-2-[(2-Fluoranyl-4-Iodanyl-Phenyl)amino]phenyl]-[3-Oxidanyl-3-[(2s)-Piperidin-2-Yl]azetidin-1-Yl]methanone [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aMino]phenyl][3-hydroxy-3-[(2S)-2-piperidinyl]-1-azetidinyl]Methanone {3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}{3-hydroxy-3-[(2S)-2-piperidinyl]-1-azetidinyl}methanone CobiMetinib Cotellic EUI GDC 0973 GDC-0973 GDC-0973(XL-518) GDC0973/XL518 Methanone, [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-[(2S)-2-piperidinyl]-1-azetidinyl]- RG 7420 RG7420 UNII:ER29L26N1X XL518 ,GDC-0973
- 1.3 CAS No.
- 934660-93-2
- 1.4 CID
- 16222096
- 1.5 Molecular Formula
- C21H21F3IN3O2 (isomer)
- 1.6 Inchi
- InChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1
- 1.7 InChkey
- BSMCAPRUBJMWDF-KRWDZBQOSA-N
- 1.8 Canonical Smiles
- C1CCNC(C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
- 1.9 Isomers Smiles
- C1CCN[C@@H](C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
2. Properties
- 2.1 Density
- 1.706
- 2.1 Boiling point
- 565.9±50.0 °C(Predicted)
- 2.1 Refractive index
- 1.662
- 2.1 Flash Point
- 296.1±30.1 °C
- 2.1 Precise Quality
- 531.06300
- 2.1 PSA
- 64.60000
- 2.1 logP
- 4.12080
- 2.1 pKa
- 13.13±0.20(Predicted)
3. Use and Manufacturing
- 3.1 Usage
- A potent, selective, orally bioavailable inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK pathway. It inhibits proliferation and stimulates apoptosis in a variety of human tumor cell lines. In preclinical xenograft models, oral administration of XL518 results in sustained inhibition of pERK in tumor tissue, but not brain tissue, leading to tumor growth inhibition and regression at well tolerated doses.
4. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
no data available
2.2 GHS label elements, including precautionary statements
| Pictogram(s) | no data available |
| Signal word | no data available |
| Hazard statement(s) | no data available |
| Precautionary statement(s) | |
| Prevention | no data available |
| Response | no data available |
| Storage | no data available |
| Disposal | no data available |
2.3 Other hazards which do not result in classification
no data available
6. Other Information
- 6.0 Target
- Value
- 6.1 MEK1 (Cell-free assay)
- 4.2 nM
- 6.2 Description
- Cobimetinib, codeveloped by Genentech and Exelixis, was approved in August 2015 in Switzerland and November 2015 in the U.S. and Europe for the treatment of unresectable or metastatic BRAFV600 mutationpositive melanoma when used in combination with vemurafenib. Cobimetinib is a potent, highly selective reversible inhibitor of mitogen-activated protein kinases (MEK) 1 and 2,120 which serves to inhibit phosphorylation of ERK1/2,121 disrupting the MAPK pathway which is responsible for cell proliferation, cell survival, and migration.122 Combination of cobimetinib with vemurafenib, an important BRAF inhibitor,123 enables targeting of multiple points on the MAPK pathway, leading to overall enhanced tumor cell apoptosis and response as compared to stand-alone treatment with vemurafenib.124 Specifically, in a representative trial of previously untreated patients with BRAFV600 mutation-positive, unresectable, stage IIIc or IV melanoma, combination of these two therapies led to a significantly improved progression-free survival and overall response rate versus patients treated only with vemurafenib.
- 6.3 Chemical Synthesis
- Structurally, cobimetinib features an interesting azetidinol substructure appended to the 2-position of a piperidine, rendering the 2-carbon of the piperidine as a stereogenic center bearing the (S)-configuration. While the early discovery routes to cobimetinib relied on a piperidine resolution-based route for accessing the cobimetinib core, the scale route to this drug employs an impressive N-cyanomethyl oxazolidine chiral auxiliary-mediated sequence to induce strereocontrol, generating the requisite stereocenter with excellent selectivity and requiring no chromatographic purification in the overall synthetic sequence. Toward this end, the most likely scale synthetic approach was initiated with deprotonation of commercially available (3S,5R,8aS)-3-phenyl-hexahydrooxazolo[ 3,2-a]pyridine-carbonitrile (180), followed by addition of commercial 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (181), yielded 182 in high purity (92%) after distillation and providing a rapid route to the core structure of cobimetinib. One-pot ring opening and reduction of 182 was accomplished by exposing this hemiaminal to acetic acid and sodium cyanoborohydride, giving rise to intermediate 183. This carbamate could be further reacted with aqueous HCl in toluene to liberate the azetidine amine salt in high purity (97.6%), which underwent immediate acylation with commercially available 2,3,4-trifluoro-benzoyl chloride (184) to enable formation of intermediate 185 in 85% purity after aqueous workup. Reductive cleavage of the chiral auxiliary of 185 with Pd/C and H2 under aqueous acidic conditions (AcOH, aq HCl) yielded the desired piperidine amine, which could be isolated as a solid (99.6% pure) after trituration with aqueous HCl. Finally, aromatic fluoride substitution with commercially available aniline 186 under basic conditions provided cobimetinib in 99.7% purity after slow precipitation from toluene (it is important to note that the authors offer no comment as to the regioselectivity of this aromatic substitution reaction). While the drug reportedly exists as a fumarate salt, no synthetic reports describing the conversion of cobimetinib to the corresponding fumarate salt were available in the chemical literature to our knowledge at the time of publication.
- 6.4 Uses
- A potent, selective, orally bioavailable inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK pathway. It inhibits proliferation and stimulates apoptosis in a variety of human tumor cell lines. In preclinical xenograft models, oral administration of XL518 results in sustained inhibition of pERK in tumor tissue, but not brain tissue, leading to tumor growth inhibition and regression at well tolerated doses.
- 6.5 Livertox Summary
- Cobimetinib is a tyrosine kinase receptor inhibitor that is used in combination with vemurafenib as therapy for selected forms of advanced malignant melanoma. The combination of cobimetinib and vemurafenib is commonly associated with serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.
- 6.6 Drug Classes
- Antineoplastic Agents
- 6.7 Absorption
- The bioavailability of cobimetinib is 46%, the AUC and Cmax is unaffected by food.|76% of the dose was recovered in feces with 6.6% as unchanged drug. 17.8% of the dose was recovered in urine with 1.6% as unchanged drug.|806L in cancer patients based on a population PK analysis.|13.9L/h
- 6.8 Metabolism
- Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed.
- 6.9 Biological Half Life
- Average half life was 44 hours.
- 6.10 Mesh Entry Terms
- (3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone
- 6.11 Use Classification
- Human drugs -> Cotellic -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
7. Computational chemical data
- Molecular Weight: 531.3100196g/mol
- Molecular Formula: C21H21F3IN3O2
- Compound Is Canonicalized: True
- XLogP3-AA: 3.9
- Exact Mass: 531.06306
- Monoisotopic Mass: 531.06306
- Complexity: 624
- Rotatable Bond Count: 4
- Hydrogen Bond Donor Count: 3
- Hydrogen Bond Acceptor Count: 7
- Topological Polar Surface Area: 64.6
- Heavy Atom Count: 30
- Defined Atom Stereocenter Count: 1
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADceB7MYAAAgAAAAAAAAAAAABYAAAAAAA8YIAAAAAAAAABQAAAHwAwCAAADGzDmAwwwIPAAgCIAiVSUACCAAAlAgAIiIEIZMgKIHrA1ZGEYYhklgDYyceYyECOAAAAAAACAAAAAAAAAAQAAAAAAAAAAA==
8. Recommended Suppliers
-
- Products:Career Henan Chemical Co, facing global High-tech pharmaceutical raw materials, high complex new type intermediates, fine chemicals custom synthesis, scale-up production and Rare chemicals trade.
- Tel:86-371-86658258
GDC-0973
- Purity:99%Packing: 200kg/bag FOB
- Price: 2 USD/kilogram
- Time: 2019/05/21
Inquire
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- Products:Pharmaceutical intermediates
- Tel:86-0-15102632950
cobimetinib
- Purity:99%Packing: 200kg/bag FOB
- Price: 1 USD/kilogram
- Time: 2022/07/08
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9. Realated Product Infomation
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