|Biological half-life||30–40 hours|
|Chemical and physical data|
|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. 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).
CERC-501 is under development for the treatment of major depressive disorder and substance use disorders including alcoholism, nicotine addiction, and illicit drug dependence. As of 2016, it has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression. 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. 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.
In December 2015, the results of a human pharmacokinetic study of CERC-501 were released. 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. Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose. At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg. No serious side effects were observed, and all side effects seen were mild to moderate and not considered to be due to CERC-501.
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.
- 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.
- 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.
- 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.
- "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.
- BusinessWire (11 December 2015). "Publication Reports Human Brain Penetration and Target Engagement of Cerecor's Oral Kappa Opioid Receptor Antagonist, CERC-501".
- 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.
- 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.
- 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.
- 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.