Zuranolone

Zuranolone (INN;[3] developmental code names SAGE-217, S-812217) is an investigational medication which is under development by SAGE Therapeutics for the treatment of depressive disorders and a variety of other indications.[4][5] It is a synthetic, orally active, inhibitory pregnane neurosteroid, and 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 (allopregnanolone), 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] As of December 2022, zuranolone is in preregistration for major depressive disorder and postpartum depression,[8] phase III clinical trials for insomnia, and phase II clinical studies for bipolar depression, essential tremor, and Parkinson's disease.[4][9] Zuranolone has also been investigated for treatment of dyskinesias and seizures, but no further development has been reported for these indications.[4]

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
  • 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)
  • 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=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

See also

References
  1. Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. (June 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 (January 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. (September 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. (December 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. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, et al. (September 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.
  9. Bullock A, Kaul I, Li S, Silber C, Doherty J, Kanes SJ (February 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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