Aticaprant

Aticaprant
Clinical data
Other namesJNJ-67953964; CERC-501; LY-2456302
Routes of
administration		By mouth[1]
Pharmacokinetic data
Bioavailability25%[1]
Elimination half-life30–40 hours[1]
Identifiers
  • 4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1-pyrrolidinyl]methyl}}phenoxy)-3-fluorobenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H27FN2O2
Molar mass418.512 g·mol−1
3D model (JSmol)
  • CC1=CC(=CC(=C1)[C@@H]2CCCN2CC3=CC=C(C=C3)OC4=C(C=C(C=C4)C(=O)N)F)C
  • InChI=1S/C26H27FN2O2/c1-17-12-18(2)14-21(13-17)24-4-3-11-29(24)16-19-5-8-22(9-6-19)31-25-10-7-20(26(28)30)15-23(25)27/h5-10,12-15,24H,3-4,11,16H2,1-2H3,(H2,28,30)/t24-/m0/s1
  • Key:ZHPMYDSXGRRERG-DEOSSOPVSA-N

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 III 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 central nervous system.[7]

Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and nicotine withdrawal, but development for these indications was discontinued.[2]

  1. ^ a b c d Cite error: The named reference pmid27213169 was invoked but never defined (see the help page).
  2. ^ a b c d e "CERC 501". Adis Insight. 30 January 2018.
  3. ^ a b Browne CA, Wulf H, Lucki I (2022). "Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder". In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 493–524. doi:10.1007/164_2020_432. ISBN 978-3-030-89073-5. PMID 33580854. S2CID 231908782.
  4. ^ a b c Reed B, Butelman ER, Kreek MJ (2022). "Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders". In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 473–491. doi:10.1007/164_2020_401. ISBN 978-3-030-89073-5. PMID 33174064. S2CID 226305229.
  5. ^ Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, Nurnberger J, Lisanby SH, et al. (May 2020). "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. doi:10.1038/s41591-020-0806-7. PMC 9949770. PMID 32231295. S2CID 256839849.
  6. ^ Dhir A (January 2017). "Investigational drugs for treating major depressive disorder". Expert Opinion on Investigational Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559. S2CID 45232796.
  7. ^ Missig G, Fritsch EL, Mehta N, Damon ME, Jarrell EM, Bartlett AA, et al. (January 2022). "Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses". Pharmacology, Biochemistry, and Behavior. 212: 173301. doi:10.1016/j.pbb.2021.173301. PMC 8748402. PMID 34826432.