Chemistry:Aticaprant
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| Other names | JNJ-67953964; CERC-501; LY-2456302 |
| Routes of administration | By mouth[1] |
| Pharmacokinetic data | |
| Bioavailability | 25%[1] |
| Elimination half-life | 30–40 hours[1] |
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| Formula | C26H27FN2O2 |
| Molar mass | 418.512 g·mol−1 |
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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.[2][3][4] A regulatory application for approval of the medication is expected to be submitted by 2025.[2] Aticaprant is taken by mouth.[1]
Side effects of aticaprant include itching, among others.[4][5] Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin.[3] 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.[4][6]
Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals.[2] As of July 2022, it is in phase 3 clinical trials for major depressive disorder.[2] 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.[7]
Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal, but development for these indications was discontinued.[2]
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).[8][9][10] 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.[10] 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.[11] In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[12]
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.[13][14] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[15][14] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[15][14] No serious side effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[14]
Pharmacokinetics
The oral bioavailability of aticaprant is 25%.[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.[13][14]
History
Aticaprant was originally developed by Eli Lilly under the code name LY-2456302.[2] It first appeared in the scientific literature in 2010 or 2011.[16][17] The compound was first patented in 2009.[18]
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).[19]
As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[20][12] 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.[14] Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.[21]
In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals.[22][21] Janssen was also experimenting with esketamine for the treatment of depression as of 2017.[21]
Research
In addition to major depressive disorder, aticaprant was under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal.[2] However, development for these indications was discontinued.[2]
See also
- κ-Opioid receptor § Antagonists
- List of investigational antidepressants
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Major Depressive Disorder and Kappa Opioid Receptor Antagonists". Translational Perioperative and Pain Medicine 1 (2): 4–16. 2016. PMID 27213169.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "CERC 501". Adis Insight. 30 January 2018. http://adisinsight.springer.com/drugs/800032395.
- ↑ 3.0 3.1 Liu-Chen, Lee-Yuan; Inan, Saadet, eds (2022). "Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder". The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. 271. pp. 493–524. doi:10.1007/164_2020_432. ISBN 978-3-030-89073-5.
- ↑ 4.0 4.1 4.2 Liu-Chen, Lee-Yuan; Inan, Saadet, eds (2022). "Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders". The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. 271. pp. 473–491. doi:10.1007/164_2020_401. ISBN 978-3-030-89073-5.
- ↑ "A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia". Nature Medicine 26 (5): 760–768. May 2020. doi:10.1038/s41591-020-0806-7. PMID 32231295.
- ↑ "Investigational drugs for treating major depressive disorder". Expert Opinion on Investigational Drugs 26 (1): 9–24. January 2017. doi:10.1080/13543784.2017.1267727. PMID 27960559.
- ↑ "Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses". Pharmacology, Biochemistry, and Behavior 212: 173301. January 2022. doi:10.1016/j.pbb.2021.173301. PMID 34826432.
- ↑ "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: 131–144. February 2014. doi:10.1016/j.neuropharm.2013.09.021. PMID 24071566.
- ↑ "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): 968–978. September 2014. doi:10.1002/jcph.286. PMID 24619932.
- ↑ 10.0 10.1 "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. October 2014. doi:10.1093/ijnp/pyu036. PMID 25637376.
- ↑ "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. March 2018. doi:10.1038/npp.2017.245. PMID 29422497.
- ↑ 12.0 12.1 "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters 24 (9): 2021–2032. May 2014. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
- ↑ 13.0 13.1 "Publication Reports Human Brain Penetration and Target Engagement of Cerecor's Oral Kappa Opioid Receptor Antagonist, CERC-501". BusinessWire. 11 December 2015. http://www.businesswire.com/news/home/20151211005042/en/Publication-Reports-Human-Brain-Penetration-Target-Engagement.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 "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): 260–266. February 2016. doi:10.1124/jpet.115.229278. PMID 26628406.
- ↑ 15.0 15.1 Liu-Chen, Lee-Yuan; Inan, Saadet, eds (August 2021). "Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography". The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. 271. pp. 547–577. doi:10.1007/164_2021_498. ISBN 978-3-030-89073-5.
- ↑ "Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging". Journal of Nuclear Medicine 54 (3): 455–463. March 2013. doi:10.2967/jnumed.112.109512. PMID 23353688.
- ↑ "Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer". Journal of Medicinal Chemistry 54 (23): 8000–8012. December 2011. doi:10.1021/jm200789r. PMID 21958337.
- ↑ "WO2009094260A1 - Kappa selective opioid receptor antagonist". 13 January 2009. https://patents.google.com/patent/WO2009094260A1/en.
- ↑ "Cerecor Bolsters Clinical Pipeline with Acquisition of Phase 2-ready Kappa Opioid Receptor Antagonist from Eli Lilly and Company". February 20, 2015. http://cerecor.com/news-publications/news-publications-press-release-2015-02-20.php.
- ↑ Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. 2012. pp. 314–317. ISBN 978-1-84973-365-6. https://books.google.com/books?id=J4Mq3Lm1R7kC&pg=PA314.
- ↑ 21.0 21.1 21.2 Bushey, Ryan (August 2017). "J&J Adds New Depression Drug to Portfolio". Drug Discovery and Development Magazine. https://www.dddmag.com/article/2017/08/j-j-adds-new-depression-drug-portfolio.
- ↑ "Cerecor Announces Divestiture of CERC-501 to Janssen Pharmaceuticals, Inc.". Marketwired. August 2017. http://markets.businessinsider.com/news/stocks/Cerecor-Announces-Divestiture-of-CERC-501-to-Janssen-Pharmaceuticals-Inc-1002255296.
Further reading
- "Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials". Depression and Anxiety 33 (10): 895–906. October 2016. doi:10.1002/da.22500. PMID 27699938.
- "Major Depressive Disorder and Kappa Opioid Receptor Antagonists". Translational Perioperative and Pain Medicine 1 (2): 4–16. 2016. PMID 27213169.
- "Investigational drugs for treating major depressive disorder". Expert Opinion on Investigational Drugs 26 (1): 9–24. January 2017. doi:10.1080/13543784.2017.1267727. PMID 27960559.
- "Endogenous opioid system in addiction and addiction-related behaviors". Current Opinion in Behavioral Sciences 13: 196–202. 2017. doi:10.1016/j.cobeha.2016.12.002. ISSN 2352-1546.
- "Beyond serotonin: newer antidepressants in the future". Expert Review of Neurotherapeutics 17 (8): 777–790. August 2017. doi:10.1080/14737175.2017.1341310. PMID 28598698.
- "Selective kappa opioid antagonists for treatment of addiction, are we there yet?". European Journal of Medicinal Chemistry 141: 632–647. December 2017. doi:10.1016/j.ejmech.2017.10.012. PMID 29107424.
- "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. Progress in Brain Research. 239. 2018. pp. 49–87. doi:10.1016/bs.pbr.2018.07.003. ISBN 9780444641670.
- "Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?". Neuronal Signaling 2 (2): NS20170145. June 2018. doi:10.1042/NS20170145. PMID 32714584.
- "Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders". Neuropsychopharmacology 43 (9): 1803–1804. August 2018. doi:10.1038/s41386-018-0046-4. PMID 29752444.
- "The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development". Nature Reviews. Drug Discovery 18 (1): 82–84. December 2018. doi:10.1038/nrd.2018.222. PMID 30591715.
- "Novel Therapeutic Targets for Major Depressive Disorder". Neurobiology of Depression. 2019. pp. 383–400. doi:10.1016/B978-0-12-813333-0.00034-2. ISBN 9780128133330.
- "Targeting opioid dysregulation in depression for the development of novel therapeutics". Pharmacology & Therapeutics 201: 51–76. September 2019. doi:10.1016/j.pharmthera.2019.04.009. PMID 31051197.
- Nader, Michael A.; Hurd, Yasmin L., eds (2020). "The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research". Substance Use Disorders. Handbook of Experimental Pharmacology. 258. pp. 147–165. doi:10.1007/164_2019_268. ISBN 978-3-030-33678-3.
- "Novel Targets to Treat Depression: Opioid-Based Therapeutics". Harvard Review of Psychiatry 28 (1): 40–59. 2020. doi:10.1097/HRP.0000000000000242. PMID 31913981.
- "Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders". Annual Review of Pharmacology and Toxicology 60: 615–636. January 2020. doi:10.1146/annurev-pharmtox-010919-023317. PMID 31914893.
- "The Therapeutic Potential of Novel Kappa Opioid Receptor-based Treatments". Current Medicinal Chemistry 27 (12): 2012–2020. 2020. doi:10.2174/0929867326666190121142459. PMID 30666905.
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