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Clinical data
Synonyms LY-2456302
Routes of
By mouth[1]
Pharmacokinetic data
Bioavailability 25%[1]
Biological half-life 30–40 hours[1]
CAS Number
PubChem CID
Chemical and physical data
Formula C26H27FN2O2
Molar mass 418.512 g/mol
3D model (JSmol)

CERC-501 (originally known as 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 substance use disorders including alcoholism, nicotine addiction, and illicit drug dependence.[2][3][4][5][6]



CERC-501 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.[7] 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.[8] In animal models of depression, CERC-501 has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[9]

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 CERC-501 is being explored in clinical trials.[6][10] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[10] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[10] No serious side effects were observed, and all side effects seen were mild to moderate and not considered to be due to CERC-501.[10]


The oral bioavailability of CERC-501 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 CERC-501 increase proportionally with increasing doses.[1] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[1] CERC-501 has been shown to reproducibly penetrate the blood–brain barrier.[6][10]


CERC-501 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 name of CERC-501).[12]

As of 2016, CERC-501 has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[13][9] A phase II study of CERC-501 in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016.[10] Unfortunately, CERC-501 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 CERC-501 to Janssen Pharmaceuticals.[15][14] Janssen is also developing esketamine (JNJ-54135419) for the treatment of depression.[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". Transl Perioper Pain Med. 1 (2): 4–16. PMC 4871611Freely accessible. PMID 27213169. 
  2. ^ a b http://adisinsight.springer.com/drugs/800032395
  3. ^ a b Rorick-Kehn LM, Witkin JM, Statnick MA, 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. 
  4. ^ a b Lowe SL, Wong CJ, Witcher J, et al. (March 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". J Clin Pharmacol. 54 (9): 968–78. doi:10.1002/jcph.286. PMID 24619932. 
  5. ^ a b Rorick-Kehn; et al. (2014). "Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 using Pupillometry as a Translational Biomarker in Rat and Human". International Journal of Neuropsychopharmacology. 18 (2): pyu036. doi:10.1093/ijnp/pyu036. 
  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. ^ Rorick-Kehn, L. M.; Witcher, J. W.; Lowe, S. L.; Gonzales, C. R.; Weller, M. A.; Bell, R. L.; Hart, J. C.; Need, A. B.; McKinzie, J. H.; Statnick, M. A.; Suico, J. G.; McKinzie, D. L.; Tauscher-Wisniewski, S.; Mitch, C. H.; Stoltz, R. R.; Wong, C. J. (2014). "Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human". International Journal of Neuropsychopharmacology. 18 (2): pyu036–pyu036. doi:10.1093/ijnp/pyu036. ISSN 1461-1457. 
  8. ^ Reed B, Butelman ER, Fry RS, Kimani R, Kreek MJ (2017). "Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence". Neuropsychopharmacology. Epub ahead of print. 
  9. ^ a b Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorg. Med. Chem. Lett. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494. 
  10. ^ a b c d e f Naganawa, M.; Dickinson, G. L.; Zheng, M.-Q.; Henry, S.; Vandenhende, F.; Witcher, J.; Bell, R.; Nabulsi, N.; Lin, S.-F.; Ropchan, J.; Neumeister, A.; Ranganathan, M.; Tauscher, J.; Huang, Y.; Carson, R. E. (2015). "Receptor Occupancy of the -Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050". Journal of Pharmacology and Experimental Therapeutics. 356 (2): 260–266. doi:10.1124/jpet.115.229278. ISSN 1521-0103. PMC 4727157Freely accessible. PMID 26628406. 
  11. ^ Zheng, M. Q.; Nabulsi, N.; Tomasi, G.; Mitch, C.; Quimby, S.; Barth, V.; Carson, R. E. (2010). "Synthesis and evaluation of [C-11] LY2795050, an antagonist PET imaging tracer for the kappa opioid receptors". NeuroImage. 52: S120. doi:10.1016/j.neuroimage.2010.04.098. 
  12. ^ "Cerecor Bolsters Clinical Pipeline with Acquisition of Phase 2-ready Kappa Opioid Receptor Antagonist from Eli Lilly and Company". cerecor.com. February 20, 2015. Retrieved March 18, 2015. 
  13. ^ Zoran Rankovic; Richard Hargreaves; Matilda Bingham (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6. 
  14. ^ a b c https://www.dddmag.com/article/2017/08/j-j-adds-new-depression-drug-portfolio
  15. ^ http://markets.businessinsider.com/news/stocks/Cerecor-Announces-Divestiture-of-CERC-501-to-Janssen-Pharmaceuticals-Inc-1002255296

External links[edit]