Dacomitinib
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| Pronunciation | dak" oh mi' ti nib |
| Trade names | Vizimpro |
| Other names | PF-00299804 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618055 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 80% |
| Protein binding | 98% |
| Metabolism | CYP2D6, CYP3A4 |
| Metabolites | O-desmethyl-dacomitinib |
| Elimination half-life | 70 hrs |
| Excretion | 79% faeces, 3% urine |
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| Formula | C24H25ClFN5O2 |
| Molar mass | 469.95 g·mol−1 |
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Dacomitinib, sold under the brand name Vizimpro, is a medication for the treatment of non-small-cell lung carcinoma (NSCLC). It is a selective and irreversible inhibitor of EGFR.[3]
Dacomitinib has advanced to several Phase III clinical trials. In January 2014, results of the first trials were disappointing, with a failure to meet the study goals,[4][5][6] but additional Phase III trials continued.[4] In 2017, results of a trial comparing dacomitinib to gefitinib for NSCLC (driven by mutated EGFR) were announced.[7]
Dacomitinib was approved for medical use in the United States in September 2018,[8] in Japan in 2019, and in the European Union in 2019;[9] for the treatment of non-small cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation.
Synthesis
The commercial process for the synthesis of dacomitinib was recently reported by Pfizer.[10] An overall yield of 58% is reported.
Catalytic hydrogenation of [1269400-04-5] (1) gave the aniline (2), which was used without purification for the next step. The reaction of methyl 4-bromocrotonate [6000-00-6] (3) with piperidine, followed by saponification of the ester gave (E)-4-(piperidin-1-yl)but-2-enoic acid [768341-84-0] (4). The amide formation between 2 & 4 was facilitated by T3P and 2,6-lutidine in acetonitrile. A reverse quench with aqueous NaOH was performed to minimize hydrolysis of the formamidine group to give PC156701138 (5). The intermediate underwent a Dimroth rearrangement in the presence of 3-chloro-4-fluoroaniline [367-21-5] (6) completing the synthesis of dacomitinib (7). It is worth noting that the intermediate as well as dacomitinib are unstable under the high temperatures typically used for Dimroth rearrangements (refluxing in HOAc). The reaction was optimized to occur at lower temperatures. The reaction was made to occur at 30 °C in neat acetic acid using two equivalents of aniline (6) to increase the reaction rate.
References
- ^ "Vizimpro Product information". Health Canada. 25 April 2012. Retrieved 29 May 2022.
- ^ "Summary Basis of Decision (SBD) for Verzenio". Health Canada. 23 October 2014. Retrieved 29 May 2022.
- ^ "Dacomitinib". NCI Drug Dictionary. National Cancer Institute, U.S. Department of Health and Human Services.
- ^ a b Chustecka Z (27 January 2014). "Dacomitinib Fails in Pretreated Non-small Cell Lung Cancer". Medscape.
- ^ Taylor P (28 January 2014). "Blow to Pfizer as dacomitinib fails in lung cancer trials". pmlive.com.
- ^ "Pfizer Announces Top-Line Results From Two Phase 3 Trials Of Dacomitinib In Patients With Refractory Advanced Non-Small Cell Lung Cancer". Pfizer Press Release. 27 January 2014.
- ^ Smith M (6 June 2017). "Dacomitinib Sets PFS Record in Phase III NSCLC Trial". MedPage Today.
- ^ Shirley M (December 2018). "Dacomitinib: First Global Approval". Drugs. 78 (18): 1947–1953. doi:10.1007/s40265-018-1028-x. PMID 30506139. S2CID 54034570.
- ^ "Vizimpro EPAR". European Medicines Agency (EMA). 5 June 2019. Retrieved 13 December 2019.
- ^ Flick, A. C., Leverett, C. A., Ding, H. X., McInturff, E., Fink, S. J., Helal, C. J., DeForest, J. C., Morse, P. D., Mahapatra, S., O’Donnell, C. J. (8 October 2020). "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry. 63 (19): 10652–10704. doi:10.1021/acs.jmedchem.0c00345.
External links
- "Dacomitinib". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 13 December 2019.