Clinical data
Routes of
ATC code None
Pharmacokinetic data
Biological half-life 30–40 hours
CAS Number 1174130-61-0
PubChem (CID) 44129648
ChemSpider 28424203
Chemical and physical data
Formula C26H27FN2O2
Molar mass 418.503 g/mol
3D model (Jmol) Interactive image

CERC-501 (originally known as LY-2456302) is a potent, selective, short-acting (non-"inactivating") antagonist of the κ-opioid receptor (KOR) (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; ~30-fold selectivity for the KOR) that was originally developed by Eli Lilly.[1][2][3] 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).[4]

CERC-501 is under development for the treatment of major depressive disorder and substance use disorders including alcoholism, nicotine addiction, and illicit drug dependence.[5] As of 2016, it has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[6][7] 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.[7] A phase II study of CERC-501 in heavy smokers will be commenced in early 2016 and results of the study are expected before the end of 2016.[8]

In December 2015, the results of a human pharmacokinetic study of CERC-501 were released.[5][8] CERC-501 was shown to reproducibly penetrate the blood-brain-barrier, and 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.[5][8] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[8] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[8] No serious side effects were observed, and all side effects seen were mild to moderate and not considered to be due to CERC-501.[8]

CERC-501 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.[9]

See also


  1. 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.
  2. 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: 968–78. doi:10.1002/jcph.286. PMID 24619932.
  3. 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". doi:10.1093/ijnp/pyu036.
  4. "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.
  5. 1 2 3 BusinessWire (11 December 2015). "Publication Reports Human Brain Penetration and Target Engagement of Cerecor's Oral Kappa Opioid Receptor Antagonist, CERC-501".
  6. 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.
  7. 1 2 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.
  8. 1 2 3 4 5 6 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.
  9. 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.

This article is issued from Wikipedia - version of the 10/31/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.