Tebanicline

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Tebanicline
Tebanicline.svg
Clinical data
ATC code
  • none
Identifiers
  • 5-{[(2R)-Azetidin-2-yl]methoxy}-2-chloropyridine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
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ChEMBL
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ECHA InfoCard 100.207.679 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H11ClN2O
Molar mass 198.65 g·mol−1
3D model (JSmol)
  • C1CN[C@H]1COC2=CN=C(C=C2)Cl
  • InChI=1S/C9H11ClN2O/c10-9-2-1-8(5-12-9)13-6-7-3-4-11-7/h1-2,5,7,11H,3-4,6H2/t7-/m1/s1 X mark.svgN
  • Key:MKTAGSRKQIGEBH-SSDOTTSWSA-N X mark.svgN
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Tebanicline (ebanicline, ABT-594) is a potent synthetic nicotinic (non-opioid) analgesic drug developed by Abbott. It was developed as a less toxic analog of the potent poison dart frog-derived compound epibatidine, which is about 200 times stronger than morphine as an analgesic, but produces extremely dangerous toxic side effects. [1] [2] Like epibatidine, tebanicline showed potent analgesic activity against neuropathic pain in both animal and human trials, but with far less toxicity than its parent compound. [3] [4] [5] [6] [7] [8] It acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes. [9]

Tebanicline progressed to Phase II clinical trials in humans, [10] but was dropped from further development due to unacceptable incidence of gastrointestinal side effects. [11] However, further research in this area is ongoing, [12] [13] [14] [15] and the development of nicotinic acetylcholine receptor agonists is ongoing. [16] [17] [18] [19] No agents from this class have successfully completed human clinical trials due to their unacceptable side effect profiles.

Ropanicant (SUVN-911)

Ropanicant (SUVN-911) Ropanicant.svg
Ropanicant (SUVN-911)

Research in the area continues. [25] For example, a new agent that is currently in phase 2b clinical trials for the treatment of depression is called ropanicant (SUVN-911).

Goldstein reported a series of agents that a based on a cyclopropane ring. [26] [27] [28] [29] The following examples are representative: PC10176364 [387844-92-0], PC15980432 & PC16662145.

References

  1. ↑ Bannon AW, Decker MW, Holladay MW, Curzon P, Donnelly-Roberts D, Puttfarcken PS, et al. (January 1998). "Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors". Science. 279 (5347): 77–81. Bibcode:1998Sci...279...77B. doi:10.1126/science.279.5347.77. PMID   9417028.
  2. ↑ Holladay MW, Wasicak JT, Lin NH, He Y, Ryther KB, Bannon AW, et al. (February 1998). "Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors". Journal of Medicinal Chemistry. 41 (4): 407–12. doi:10.1021/jm9706224. PMID   9484491.
  3. ↑ Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, et al. (May 1998). "ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 777–86. PMID   9580626.
  4. ↑ Bannon AW, Decker MW, Curzon P, Buckley MJ, Kim DJ, Radek RJ, et al. (May 1998). "ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 787–94. PMID   9580627.
  5. ↑ Decker MW, Bannon AW, Buckley MJ, Kim DJ, Holladay MW, Ryther KB, et al. (April 1998). "Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice". European Journal of Pharmacology. 346 (1): 23–33. doi:10.1016/S0014-2999(98)00042-9. PMID   9617748.
  6. ↑ Kesingland AC, Gentry CT, Panesar MS, Bowes MA, Vernier JM, Cube R, et al. (May 2000). "Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain". Pain. 86 (1–2): 113–8. doi:10.1016/s0304-3959(00)00233-5. PMID   10779668. S2CID   26170267.
  7. ↑ Sorbera LA, Revel L, Leeson P, Castaner J (2001). "ABT-594". Drugs of the Future. 26 (10): 927. doi:10.1358/dof.2001.026.10.640317.
  8. ↑ Lynch JJ, Wade CL, Mikusa JP, Decker MW, Honore P (February 2005). "ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model". European Journal of Pharmacology. 509 (1): 43–8. doi:10.1016/j.ejphar.2004.12.034. PMID   15713428.
  9. ↑ Jain KK (January 2004). "Modulators of nicotinic acetylcholine receptors as analgesics". Current Opinion in Investigational Drugs. 5 (1): 76–81. PMID   14983978.
  10. ↑ Decker MW, Meyer MD, Sullivan JP (October 2001). "The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control". Expert Opinion on Investigational Drugs. 10 (10): 1819–30. doi:10.1517/13543784.10.10.1819. PMID   11772288. S2CID   24924290.
  11. ↑ Meyer MD (1 April 2006). "Neuronal nicotinic acetylcholine receptors as a target for the treatment of neuropathic pain". Drug Development Research. 67 (4): 355–359. doi:10.1002/ddr.20099. ISSN   1098-2299. S2CID   84222640.
  12. ↑ Baraznenok IL, Jonsson E, Claesson A (March 2005). "3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity". Bioorganic & Medicinal Chemistry Letters. 15 (6): 1637–40. doi:10.1016/j.bmcl.2005.01.058. PMID   15745813.
  13. ↑ Zhang CX, Ge ZM, Cheng TM, Li RT (April 2006). "Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594". Bioorganic & Medicinal Chemistry Letters. 16 (7): 2013–6. doi:10.1016/j.bmcl.2005.12.073. PMID   16412637.
  14. ↑ Bunnelle WH, Daanen JF, Ryther KB, Schrimpf MR, Dart MJ, Gelain A, et al. (July 2007). "Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors". Journal of Medicinal Chemistry. 50 (15): 3627–44. doi:10.1021/jm070018l. PMID   17585748.
  15. ↑ Joshi SK, Mikusa JP, Weaver B, Honore P (February 2008). "Morphine and ABT-594 (a nicotinic acetylcholine agonist) exert centrally mediated antinociception in the rat cyclophosphamide cystitis model of visceral pain". The Journal of Pain. 9 (2): 146–56. doi: 10.1016/j.jpain.2007.09.004 . PMID   18088559.
  16. ↑ Lloyd GK, Williams M (2000). "Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets". Journal of Pharmacology and Experimental Therapeutics. 292 (2): 461–467. PMID   10640281.
  17. ↑ Vincler M (October 2005). "Neuronal nicotinic receptors as targets for novel analgesics". Expert Opinion on Investigational Drugs. 14 (10): 1191–8. doi:10.1517/13543784.14.10.1191. PMID   16185161. S2CID   20618128.
  18. ↑ Arneric SP, Holladay M, Williams M (October 2007). "Neuronal nicotinic receptors: a perspective on two decades of drug discovery research". Biochemical Pharmacology. Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science. 74 (8): 1092–101. doi:10.1016/j.bcp.2007.06.033. PMID   17662959.
  19. ↑ Wells GB (May 2008). "Structural answers and persistent questions about how nicotinic receptors work". Frontiers in Bioscience. 13 (13): 5479–510. doi:10.2741/3094. PMC   2430769 . PMID   18508600.
  20. ↑ Nirogi, Ramakrishna; Mohammed, Abdul Rasheed; Shinde, Anil K.; Ravella, Srinivasa Rao; Bogaraju, Narsimha; Subramanian, Ramkumar; Mekala, Venkat Reddy; Palacharla, Raghava Choudary; Muddana, Nageswararao; Thentu, Jagadeesh Babu; Bhyrapuneni, Gopinadh; Abraham, Renny; Jasti, Venkat (2020). "Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression". Journal of Medicinal Chemistry. 63 (6): 2833–2853. doi:10.1021/acs.jmedchem.9b00790.
  21. ↑ "Synthesis of SUVN-911". Synfacts. 16 (06): 0626. 2020. doi:10.1055/s-0040-1707534.
  22. ↑ Ramakrishna Nirogi, et al. WO2011061751 (Suven Life Sciences Ltd).
  23. ↑ Nirogi R, Benade V, Goyal VK, Pandey SK, Mohammed AR, Shinde A, Dogiparti D, Ravula J, Jetta S, Palacharla VRC. Safety, Tolerability, and Pharmacokinetics of Ropanicant (SUVN-911), a Novel Alpha4 Beta2 Nicotinic Acetylcholine Receptor (α4β2 nAChR) Antagonist, in Healthy Adult and Elderly Subjects. Clin Drug Investig. 2022 Sep;42(9):747-762. doi: 10.1007/s40261-022-01189-9. Epub 2022 Aug 13. PMID: 35963959.
  24. ↑ Nirogi R, Abraham R, Jayarajan P, Goura V, Kallepalli R, Medapati RB, Tadiparthi J, Goyal VK, Pandey SK, Subramanian R, Petlu S, Thentu JB, Palacharla VRC, Gagginapally SR, Mohammed AR, Jasti V. Ropanicant (SUVN-911), an α4β2 nicotinic acetylcholine receptor antagonist intended for the treatment of depressive disorders: pharmacological, behavioral, and neurochemical characterization. Psychopharmacology (Berl). 2022 Jul;239(7):2215-2232. doi: 10.1007/s00213-022-06108-6. Epub 2022 Mar 17. PMID: 35298691.
  25. ↑ Umana IC, Daniele CA, McGehee DS (Oct 2013). "Neuronal nicotinic receptors as analgesic targets: it's a winding road". Biochem Pharmacol. 86 (8): 1208–14. doi:10.1016/j.bcp.2013.08.001. PMC   4127197 . PMID   23948066.
  26. ↑ Solo Goldstein, et al. U.S. patent 6,943,184 (2002 to ADIR SARL, Laboratoires Servier SAS).
  27. ↑ Charton Y, Guillonneau C, Lockhart B, Lestage P, Goldstein S. Preparation and affinity profile of novel nico-tinic ligands. Bioorg Med Chem Lett. 2008 Mar 15;18(6):2188-93. doi: 10.1016/j.bmcl.2007.12.075. Epub 2008 Jan 26. PMID: 18262785.
  28. ↑ US7348344 idem Solo Goldstein, et al. WO2007012762 (Laboratoires Servier SAS).
  29. ↑ Solo Goldstein, et al. WO2007085750 (to Laboratoires Servier SAS).
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