Zuranolone

Zuranolone (INN;[3] developmental code names SAGE-217, S-812217) is an investigational drug which is under development by SAGE Therapeutics for the treatment of depressive disorders and a variety of other indications.[4][5] An orally active inhibitory pregnane neurosteroid, zuranolone acts as a positive allosteric modulator of the GABAA receptor.[4][5][6] The drug was developed as an improvement on the intravenously administered neurosteroid brexanolone, with high oral bioavailability and a biological half-life suitable for once-daily administration.[5][7] Its half-life is around 16 to 23 hours, compared to approximately 9 hours for brexanolone.[1][2]

Zuranolone
Clinical data
Other namesSAGE-217; S-812217; SGE-797; BIIB-125; 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one; 3β-Methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-norpregnanolone; 3α-Hydroxy-3β-methyl-5β-dihydro-21-(4-cyano-1H-pyrazol-1'-yl)-19-norprogesterone
Routes of
administration		By mouth
Drug classNeurosteroid; GABAA receptor positive allosteric modulator
Pharmacokinetic data
Elimination half-life16–23 hours[1][2]
Identifiers
IUPAC name
  • 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC25H35N3O2
Molar mass409.574 g·mol−1
3D model (JSmol)
SMILES
  • O=C(CN1N=CC(C#N)=C1)[C@H]2CC[C@@]3([H])[C@]4([H])CC[C@]5([H])C[C@](C)(O)CC[C@]5([H])[C@@]4([H])CC[C@@]32C
InChI
  • InChI=1S/C25H35N3O2/c1-24(30)9-7-18-17(11-24)3-4-20-19(18)8-10-25(2)21(20)5-6-22(25)23(29)15-28-14-16(12-26)13-27-28/h13-14,17-22,30H,3-11,15H2,1-2H3/t17-,18+,19-,20-,21+,22-,24-,25+/m1/s1
  • Key:HARRKNSQXBRBGZ-GVKWWOCJSA-N

Medical uses

In a randomized, placebo‐controlled phase 3 trial to assess its efficacy and safety for the treatment of major depressive disorder, subjects in the zuranolone group (50 mg oral zuranolone once daily for 14 days) experienced statistically significant and sustained improvements in depressive symptoms (as measured by HAM-D score) throughout the treatment and follow-up periods of the study.[8]

Other investigational applications include postpartum depression,[9] insomnia, bipolar depression, essential tremor, and Parkinson's disease.[4][10]

See also

References
  1. Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. (2022). "GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors". Pharmacology & Therapeutics. 234: 108035. doi:10.1016/j.pharmthera.2021.108035. PMC 9787737. PMID 34793859. S2CID 244280839.
  2. Faden J, Citrome L (2020). "Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used?". Therapeutic Advances in Psychopharmacology. 10: 2045125320968658. doi:10.1177/2045125320968658. PMC 7656877. PMID 33224470.
  3. "International Nonproprietary Names for Pharmaceutical Substances" (PDF). WHO Drug Information. 32 (4). 2018.
  4. "SAGE 217". AdisInsight. Retrieved 2018-02-10.
  5. Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, Salituro FG (2018). "Breakthroughs in neuroactive steroid drug discovery". Bioorganic & Medicinal Chemistry Letters. 28 (2): 61–70. doi:10.1016/j.bmcl.2017.11.043. PMID 29223589.
  6. Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, et al. (2017). "Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor". Journal of Medicinal Chemistry. 60 (18): 7810–7819. doi:10.1021/acs.jmedchem.7b00846. PMID 28753313.
  7. Althaus AL, Ackley MA, Belfort GM, Gee SM, Dai J, Nguyen DP, et al. (2020). "Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator". Neuropharmacology. 181: 108333. doi:10.1016/j.neuropharm.2020.108333. PMC 8265595. PMID 32976892.
  8. Clayton AH, Lasser R, Parikh SV, Iosifescu DV, Jung J, Kotecha M, et al. (May 2023). "Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial". The American Journal of Psychiatry: appiajp20220459. doi:10.1176/appi.ajp.20220459. PMID 37132201. S2CID 258461851.
  9. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, et al. (2021). "Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial". JAMA Psychiatry. 78 (9): 951–959. doi:10.1001/jamapsychiatry.2021.1559. PMC 8246337. PMID 34190962.
  10. Bullock A, Kaul I, Li S, Silber C, Doherty J, Kanes SJ (2021). "Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study". Journal of the Neurological Sciences. 421: 117277. doi:10.1016/j.jns.2020.117277. PMID 33387701. S2CID 229333842.
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