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Clinical data
Other namesJNJ-67953964; CERC-501; LY-2456302
Routes of
By mouth[1]
Pharmacokinetic data
Elimination half-life30–40 hours[1]
  • 4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1-pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide
CAS Number
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
Molar mass418.512 g·mol−1
3D model (JSmol)
  • CC1=CC(=CC(=C1)[C@@H]2CCCN2CC3=CC=C(C=C3)OC4=C(C=C(C=C4)C(=O)N)F)C
  • InChI=1S/C26H27FN2O2/c1-17-12-18(2)14-21(13-17)24-4-3-11-29(24)16-19-5-8-22(9-6-19)31-25-10-7-20(26(28)30)15-23(25)27/h5-10,12-15,24H,3-4,11,16H2,1-2H3,(H2,28,30)/t24-/m0/s1

Aticaprant (developmental codes JNJ-67953964, CERC-501, and LY-2456302) is a selective antagonist of the κ-opioid receptor (KOR) which was originally developed by Eli Lilly and is now under development by Janssen Pharmaceuticals for the treatment of major depressive disorder and smoking withdrawal.[2][3][4][5][6]



Aticaprant is a potent, selective, short-acting (i.e., non-"inactivating") antagonist of the KOR (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; approximately 30-fold selectivity for the KOR).[3][4][5] The drug has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), suggesting that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[5] However, a more recent study assessing neuroendocrine effects of the drug in normal volunteers and subjects with a history of cocaine dependence reported observations consistent with modest MOR antagonism at the 10 mg dose.[7] In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[8]

Positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that aticaprant is being explored at in clinical trials.[6][9] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[10][9] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[10][9] No serious side effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[9]


The oral bioavailability of aticaprant is 25% and is regarded as good.[1] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.[1] It has an elimination half-life of 30 to 40 hours in healthy subjects.[1] The circulating levels of aticaprant increase proportionally with increasing doses.[1] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[1] Aticaprant has been shown to reproducibly penetrate the blood–brain barrier.[6][9]


Aticaprant was originally developed by Eli Lilly under the code name LY-2456302.[2] It first appeared in the scientific literature in 2010.[11]

In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code CERC-501).[12]

As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[13][8] A phase II study of aticaprant in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016.[9] Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.[14]

In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals.[15][14] Janssen was also experimenting with esketamine for the treatment of depression as of 2017.[14]

See also[edit]


  1. ^ a b c d e f g h Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, Shao L, Qiu Z (2016). "Major Depressive Disorder and Kappa Opioid Receptor Antagonists". Translational Perioperative and Pain Medicine. 1 (2): 4–16. PMC 4871611. PMID 27213169.
  2. ^ a b "CERC 501". Adis Insight. 30 January 2018.
  3. ^ a b Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. (February 2014). "LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders". Neuropharmacology. 77: 131–44. doi:10.1016/j.neuropharm.2013.09.021. PMID 24071566. S2CID 3230414.
  4. ^ a b Lowe SL, Wong CJ, Witcher J, Gonzales CR, Dickinson GL, Bell RL, et al. (September 2014). "Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects". Journal of Clinical Pharmacology. 54 (9): 968–78. doi:10.1002/jcph.286. PMID 24619932. S2CID 14814449.
  5. ^ a b c Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, et al. (October 2014). "Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human". The International Journal of Neuropsychopharmacology. 18 (2): pyu036. doi:10.1093/ijnp/pyu036. PMC 4368892. PMID 25637376.
  6. ^ a b c BusinessWire (11 December 2015). "Publication Reports Human Brain Penetration and Target Engagement of Cerecor's Oral Kappa Opioid Receptor Antagonist, CERC-501".
  7. ^ Reed B, Butelman ER, Fry RS, Kimani R, Kreek MJ (March 2018). "Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence". Neuropsychopharmacology. 43 (4): 928. doi:10.1038/npp.2017.245. PMC 5809790. PMID 29422497.
  8. ^ a b Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
  9. ^ a b c d e f Naganawa M, Dickinson GL, Zheng MQ, Henry S, Vandenhende F, Witcher J, et al. (February 2016). "Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050". The Journal of Pharmacology and Experimental Therapeutics. 356 (2): 260–6. doi:10.1124/jpet.115.229278. PMC 4727157. PMID 26628406.
  10. ^ a b Placzek MS (August 2021). "Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 271: 547–577. doi:10.1007/164_2021_498. ISBN 978-3-030-89073-5. PMID 34363128. S2CID 236947969.
  11. ^ Zheng MQ, Nabulsi N, Kim SJ, Tomasi G, Lin SF, Mitch C, et al. (March 2013). "Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging". Journal of Nuclear Medicine. 54 (3): 455–63. doi:10.2967/jnumed.112.109512. PMC 3775344. PMID 23353688.
  12. ^ "Cerecor Bolsters Clinical Pipeline with Acquisition of Phase 2-ready Kappa Opioid Receptor Antagonist from Eli Lilly and Company". February 20, 2015. Archived from the original on 2015-02-23. Retrieved March 18, 2015.
  13. ^ Rankovic Z, Hargreaves R, Bingham M (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6.
  14. ^ a b c Bushey R (August 2017). "J&J Adds New Depression Drug to Portfolio". Drug Discovery and Development Magazine.
  15. ^ "Cerecor Announces Divestiture of CERC-501 to Janssen Pharmaceuticals, Inc". Marketwired. August 2017.

Further reading[edit]

External links[edit]