Biricodar

Biricodar
Clinical data
ATC code
  • none
Identifiers
  • 1,7-di(pyridin-3-yl)heptan-4-yl (2S)-1-[oxo(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC34H41N3O7
Molar mass603.716 g·mol−1
3D model (JSmol)
  • O=C(C(=O)c1cc(OC)c(OC)c(OC)c1)N4[C@H](C(=O)OC(CCCc2cccnc2)CCCc3cccnc3)CCCC4
  • InChI=1S/C34H41N3O7/c1-41-29-20-26(21-30(42-2)32(29)43-3)31(38)33(39)37-19-5-4-16-28(37)34(40)44-27(14-6-10-24-12-8-17-35-22-24)15-7-11-25-13-9-18-36-23-25/h8-9,12-13,17-18,20-23,27-28H,4-7,10-11,14-16,19H2,1-3H3/t28-/m0/s1 Y
  • Key:CGVWPQOFHSAKRR-NDEPHWFRSA-N Y
  (verify)

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. 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. Archived from the original on 2026-02-17.
  2. ^ Yang Q, Luo K, To KK, Pan C, Fu K, Zhu S, et al. (December 2025). "KSQ-4279, an Inhibitor of Ubiquitin Specific Peptidase 1, Enhanced the Chemotherapeutic Efficacy in ABCB1/ABCG2/ABCC1-Mediated Multidrug Resistant Cancers". MedComm. 6 (12) e70517. doi:10.1002/mco2.70517. PMC 12664909. PMID 41328326.
  3. ^ Stefan SM (September 2019). "Multi-target ABC transporter modulators: what next and where to go?". Future Medicinal Chemistry. 11 (18): 2353–2358. doi:10.4155/fmc-2019-0185. PMID 31516029.
  4. ^ Veitch M, Beaumont K, Pouwer R, Chew HY, Frazer IH, Soyer HP, et al. (September 2023). "Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts". Journal for Immunotherapy of Cancer. 11 (9) e006783. doi:10.1136/jitc-2023-006783. PMC 10496666. PMID 37678918.
  5. ^ Kambli L, Bhatt LK, Oza M, Prabhavalkar K (October 2017). "Novel therapeutic targets for epilepsy intervention". Seizure. 51: 27–34. doi:10.1016/j.seizure.2017.07.014. PMID 28772199.
  6. ^ US patent 5723459, Armistead DM, Harding MW, Saunders JO, Boger JS, "Biologically active acylated amino acid derivatives", issued 1998-03-03, assigned to Vertex Pharmaceuticals Incorporated 
  7. ^ Peck RA, Hewett J, Harding MW, Wang YM, Chaturvedi PR, Bhatnagar A, et al. (June 2001). "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. doi:10.1200/JCO.2001.19.12.3130. PMID 11408511.
  8. ^ Dey S (May 2002). "Biricodar. Vertex Pharmaceuticals". Current Opinion in Investigational Drugs. 3 (5): 818–823. PMID 12090559.
  9. ^ Seiden MV, Swenerton KD, Matulonis U, Campos S, Rose P, Batist G, et al. (September 2002). "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. doi:10.1006/gyno.2002.6762. PMID 12217752.
  10. ^ Gandhi L, Harding MW, Neubauer M, Langer CJ, Moore M, Ross HJ, et al. (March 2007). "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. doi:10.1002/cncr.22492. PMID 17285598.
  11. ^ a b c Daniel Lednicer (2008). Organic Chemistry of Drug Synthesis. Vol. 7. Hoboken, NJ: John Wiley & Sons. p. 119. ISBN 978-0-470-10750-8.
  12. ^ Stivanello M, Leoni L, Bortolaso R (2002). "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. doi:10.1021/op020050j.
  13. ^ Germann UA, Shlyakhter D, Mason VS, Zelle RE, Duffy JP, Galullo V, et al. (February 1997). "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. doi:10.1097/00001813-199702000-00004. PMID 9073309.
  14. ^ Germann UA, Ford PJ, Shlyakhter D, Mason VS, Harding MW (February 1997). "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. doi:10.1097/00001813-199702000-00005. PMID 9073310.
  15. ^ Minderman H, O'Loughlin KL, Pendyala L, Baer MR (March 2004). "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. doi:10.1158/1078-0432.ccr-0914-3. PMID 15014037.
  16. ^ Xu K, Zhang Q, Chen M, Li B, Wang N, Li C, et al. (April 2022). "N6-methyladenosine modification regulates imatinib resistance of gastrointestinal stromal tumor by enhancing the expression of multidrug transporter MRP1". Cancer Letters. 530: 85–99. doi:10.1016/j.canlet.2022.01.008. PMID 35032557.

Further reading

  • Nobili S, Landini I, Giglioni B, Mini E (July 2006). "Pharmacological strategies for overcoming multidrug resistance". Current Drug Targets. 7 (7): 861–879. doi:10.2174/138945006777709593. PMID 16842217.
  • Toppmeyer D, Seidman AD, Pollak M, Russell C, Tkaczuk K, Verma S, et al. (March 2002). "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. PMID 11895894.
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