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| Other names | JNJ-67953964; CERC-501; LY-2456302 |
| Routes of administration |
By mouth |
| Pharmacokinetic data | |
| Bioavailability | 25% |
| Elimination half-life | 30–40 hours |
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| CAS Number | |
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| IUPHAR/BPS | |
| DrugBank | |
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| Chemical and physical data | |
| Formula | C26H27FN2O2 |
| Molar mass | 418.512 g·mol−1 |
| 3D model (JSmol) | |
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Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder. A regulatory application for approval of the medication is expected to be submitted by 2025. Aticaprant is taken by mouth.
Side effects of aticaprant include itching, among others. Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin. The medication has decent selectivity for the KOR over the μ-opioid receptor (MOR) and other targets, a relatively long half-life of 30 to 40 hours, and readily crosses the blood–brain barrier to produce central effects.
Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals. As of July 2022, it is in phase 3 clinical trials for major depressive disorder. Like other kappa opioid antagonists currently under clinical investigation for the treatment of major depression, its efficacy may be compromised by the countervailing activation of pro-inflammatory cytokines in microglia within the CNS.
Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal, but development for these indications was discontinued.
Pharmacology
Pharmacodynamics
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). 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. 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. In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.
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. 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 were not thought to be due to aticaprant.
Pharmacokinetics
The oral bioavailability of aticaprant is 25%. The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration. It has an elimination half-life of 30 to 40 hours in healthy subjects. The circulating levels of aticaprant increase proportionally with increasing doses.Steady-state concentrations are reached after 6 to 8 days of once-daily dosing. Aticaprant has been shown to reproducibly penetrate the blood–brain barrier.
History
Aticaprant was originally developed by Eli Lilly under the code name LY-2456302. It first appeared in the scientific literature in 2010 or 2011. The compound was first patented in 2009.
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).
As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression. 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. Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.
In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals. Janssen was also experimenting with esketamine for the treatment of depression as of 2017.
Research
In addition to major depressive disorder, aticaprant was under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal. However, development for these indications was discontinued.
See also
Further reading
- Carlezon WA, Krystal AD (October 2016). "Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials". Depress Anxiety. 33 (10): 895–906. doi:10.1002/da.22500. PMC 5288841. PMID 27699938.
- 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 4871611. PMID 27213169.
- Dhir A (January 2017). "Investigational drugs for treating major depressive disorder". Expert Opin Investig Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559. S2CID 45232796.
- Reed, Brian; Butelman, Eduardo R; Kreek, Mary Jeanne (2017). "Endogenous opioid system in addiction and addiction-related behaviors". Current Opinion in Behavioral Sciences. 13: 196–202. doi:10.1016/j.cobeha.2016.12.002. ISSN 2352-1546. S2CID 53149180.
- Rakesh G, Pae CU, Masand PS (August 2017). "Beyond serotonin: newer antidepressants in the future". Expert Rev Neurother. 17 (8): 777–790. doi:10.1080/14737175.2017.1341310. PMID 28598698. S2CID 205823807.
- Helal MA, Habib ES, Chittiboyina AG (December 2017). "Selective kappa opioid antagonists for treatment of addiction, are we there yet?". Eur J Med Chem. 141: 632–647. doi:10.1016/j.ejmech.2017.10.012. PMID 29107424.
- McHugh KL, Kelly JP (2018). "Modulation of the central opioid system as an antidepressant target in rodent models". The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems. Prog. Brain Res. Progress in Brain Research. Vol. 239. pp. 49–87. doi:10.1016/bs.pbr.2018.07.003. ISBN 9780444641670. PMID 30314569.
- Bailey, Sarah J.; Husbands, Stephen M. (2018). "Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?". Neuronal Signaling. 2 (2): NS20170145. doi:10.1042/NS20170145. ISSN 2059-6553. PMC 7373229. PMID 32714584.
- Chavkin C (August 2018). "Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders". Neuropsychopharmacology. 43 (9): 1803–1804. doi:10.1038/s41386-018-0046-4. PMC 6046055. PMID 29752444.
- Krystal AD, Pizzagalli DA, Mathew SJ, Sanacora G, Keefe R, Song A, Calabrese J, Goddard A, Goodman W, Lisanby SH, Smoski M, Weiner R, Iosifescu D, Nurnberger J, Szabo S, Murrough J, Shekhar A, Potter W (December 2018). "The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development". Nat Rev Drug Discov. 18 (1): 82–84. doi:10.1038/nrd.2018.222. PMC 6816017. PMID 30591715.
- Lazar, Max A.; McIntyre, Roger S. (2019). "Novel Therapeutic Targets for Major Depressive Disorder". Neurobiology of Depression. pp. 383–400. doi:10.1016/B978-0-12-813333-0.00034-2. ISBN 9780128133330. S2CID 86782597.
- Browne CA, Lucki I (September 2019). "Targeting opioid dysregulation in depression for the development of novel therapeutics". Pharmacol. Ther. 201: 51–76. doi:10.1016/j.pharmthera.2019.04.009. PMC 6859062. PMID 31051197.
- Banks ML (2020). "The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 258: 147–165. doi:10.1007/164_2019_268. ISBN 978-3-030-33678-3. PMC 7756963. PMID 31463605.
- Browne CA, Jacobson ML, Lucki I (2020). "Novel Targets to Treat Depression: Opioid-Based Therapeutics". Harv Rev Psychiatry. 28 (1): 40–59. doi:10.1097/HRP.0000000000000242. PMID 31913981. S2CID 210120636.
- Jacobson ML, Browne CA, Lucki I (January 2020). "Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders". Annu. Rev. Pharmacol. Toxicol. 60: 615–636. doi:10.1146/annurev-pharmtox-010919-023317. PMID 31914893.
- Mercadante S, Romualdi P (2020). "The Therapeutic Potential of Novel Kappa Opioid Receptor-based Treatments". Curr. Med. Chem. 27 (12): 2012–2020. doi:10.2174/0929867326666190121142459. PMID 30666905. S2CID 58558833.