Chemistry:Biricodar

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Biricodar (INN, codename VX-710, brand name Incel) was a pharmaceutical drug under development by Vertex Pharmaceuticals to help treat antineoplastic resistance in cancer.[1]

Biricodar is considered a second-generation ABC transporter inhibitor[2] and has been described as one of the most famous foundational drugs of this class.[3] Although it has not been brought to market, biricodar continues to be used in basic research[4] and is a compound of interest for potential clinical applications.[5]

History

Biricodar was patented in 1998 by Vertex Pharmaceuticals for the treatment of multi-drug antineoplastic resistance in cancer.[6] Following a Phase I clinical trial,[7] Phase II trials commenced in 1998 to administer biricodar alongside chemotherapy in the treatment of five common cancer indications.[8] While biricodar showed modest effectiveness in one clinical trial,[9] another clinical trial was terminated for failing to enhance antitumor activity or patient survival,[10] and the drug never reached the market.

Synthesis

Biricodar is produced by esterification after convergent synthesis of the N-acyl pipecolic acid and dipyridyl 4-heptanol.[11]

A simplified route to the pipecolic acid begins with oxidation of trimethoxyacetophenone to the carboxylic acid, which is then condensed with trimethylsilyl pipecolate to yield an amide. Deprotection of the pipecolate yields the acid.[11]

Production of the alcohol begins with propargylation of 3-butynal yielding 1,6-heptadiyn-4-ol.[better source needed] The terminal alkynes of the diynol are deprotonated by strong base, and the resulting acetylides displace bromide from 3-bromopyridine. Finally, hydrogenation of the alkynes yields 1,7-dipyridyl-4-heptanol.[11] An alternative route proceeds via the Wittig reagent bis(triphenylphosphonium)pentan-3-ol and pyridine-3-carbaldehyde.[12]

Mechanism

Biricodar has been used in cancer research as an inhibitor of P-glycoprotein[13] and the ABC transporter MRP-1[14]. These membrane proteins are overexpressed in antineoplastic resistant cancer cells.[15][16] It is owing to this mechanism that biricodar was developed for the treatment of antineoplastic resistance in cancer.

References

  1. ↑ "Vertex' MDR Inhibitor Incel". The Pharma Letter. 1998-07-28. https://www.thepharmaletter.com/vertex-mdr-inhibitor-incel. 
  2. ↑ "KSQ-4279, an Inhibitor of Ubiquitin Specific Peptidase 1, Enhanced the Chemotherapeutic Efficacy in ABCB1/ABCG2/ABCC1-Mediated Multidrug Resistant Cancers". MedComm 6 (12). December 2025. doi:10.1002/mco2.70517. PMID 41328326. 
  3. ↑ "Multi-target ABC transporter modulators: what next and where to go?". Future Medicinal Chemistry 11 (18): 2353–2358. September 2019. doi:10.4155/fmc-2019-0185. PMID 31516029. 
  4. ↑ "Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts". Journal for Immunotherapy of Cancer 11 (9). September 2023. doi:10.1136/jitc-2023-006783. PMID 37678918. 
  5. ↑ "Novel therapeutic targets for epilepsy intervention". Seizure 51: 27–34. October 2017. doi:10.1016/j.seizure.2017.07.014. PMID 28772199. 
  6. ↑ Armistead DM, Harding MW, Saunders JO, Boger JS, "Biologically active acylated amino acid derivatives", US patent 5723459, issued 1998-03-03, assigned to Vertex Pharmaceuticals Incorporated
  7. ↑ "Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin". Journal of Clinical Oncology 19 (12): 3130–3141. June 2001. doi:10.1200/JCO.2001.19.12.3130. PMID 11408511. 
  8. ↑ "Biricodar. Vertex Pharmaceuticals". Current Opinion in Investigational Drugs 3 (5): 818–823. May 2002. PMID 12090559. 
  9. ↑ "A phase II study of the MDR inhibitor biricodar (INCEL, VX-710) and paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy". Gynecologic Oncology 86 (3): 302–310. September 2002. doi:10.1006/gyno.2002.6762. PMID 12217752. 
  10. ↑ "A phase II study of the safety and efficacy of the multidrug resistance inhibitor VX-710 combined with doxorubicin and vincristine in patients with recurrent small cell lung cancer". Cancer 109 (5): 924–932. March 2007. doi:10.1002/cncr.22492. PMID 17285598. 
  11. ↑ 11.0 11.1 11.2 Daniel Lednicer (2008). Organic Chemistry of Drug Synthesis. 7. Hoboken, NJ: John Wiley & Sons. p. 119. ISBN 978-0-470-10750-8. 
  12. ↑ "Synthesis of 1,5-Bis(triphenylphosphonium)pentan-3-ol Dichloride and Its Application to the Preparation of 1,7-Di(pyridin-3-yl)heptan-4-ol". Organic Process Research & Development 6 (6): 807–810. 2002. doi:10.1021/op020050j. 
  13. ↑ "Cellular and biochemical characterization of VX-710 as a chemosensitizer: reversal of P-glycoprotein-mediated multidrug resistance in vitro". Anti-Cancer Drugs 8 (2): 125–140. February 1997. doi:10.1097/00001813-199702000-00004. PMID 9073309. 
  14. ↑ "Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP". Anti-Cancer Drugs 8 (2): 141–155. February 1997. doi:10.1097/00001813-199702000-00005. PMID 9073310. 
  15. ↑ "VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein". Clinical Cancer Research 10 (5): 1826–1834. March 2004. doi:10.1158/1078-0432.ccr-0914-3. PMID 15014037. 
  16. ↑ "N6-methyladenosine modification regulates imatinib resistance of gastrointestinal stromal tumor by enhancing the expression of multidrug transporter MRP1". Cancer Letters 530: 85–99. April 2022. doi:10.1016/j.canlet.2022.01.008. PMID 35032557. 

Further reading

  • "Pharmacological strategies for overcoming multidrug resistance". Current Drug Targets 7 (7): 861–879. July 2006. doi:10.2174/138945006777709593. PMID 16842217. 
  • "Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel". Clinical Cancer Research 8 (3): 670–678. March 2002. PMID 11895894. 



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