Zuranolone

Zuranolone

CAS 1632051-40-1

Zurzuvae

FDA APPROVED 8/4/2023, To treat postpartum depression
Press Release

WeightAverage: 409.574
Monoisotopic: 409.272927379Chemical FormulaC₂₅H₃₅N₃O₂

• SAGE 217
• SAGE-217
• SAGE217

Zuranolone, sold under the brand name Zurzuvae, is a medication used for the treatment of postpartum depression.^[1][2] It is taken by mouth.^[1]

The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.^[1][2] An orally active inhibitory pregnane neurosteroid, zuranolone acts as a positive allosteric modulator of the GABA_A receptor.^[6][7][8]

Zuranolone was approved for medical use in the United States for the treatment of postpartum depression in August 2023.^[2] It was developed by Sage Therapeutics and Biogen.^[9]

Medical uses

Zuranolone is indicated for the treatment of postpartum depression.^[1][2]

Adverse effects

The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis (cold-like symptoms), and urinary tract infection.^[2]

The US FDA label contains a boxed warning noting that zuranolone can impact a person’s ability to drive and perform other potentially hazardous activities.^[2] Use of zuranolone may cause suicidal thoughts and behavior.^[2] Zuranolone may cause fetal harm.^[2]

History

Zuranolone 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.^[7][10] Its half-life is around 16 to 23 hours, compared to approximately 9 hours for brexanolone.^[4][5]

The efficacy of zuranolone for the treatment of postpartum depression in adults was demonstrated in two randomized, double-blind, placebo-controlled, multicenter studies.^[2] The trial participants were women with postpartum depression who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode and whose symptoms began in the third trimester or within four weeks of delivery.^[2] In study 1, participants received 50 mg of zuranolone or placebo once daily in the evening for 14 days.^[2] In study 2, participants received another zuranolone product that was approximately equal to 40 mg of zuranolone or placebo, also for 14 days.^[2] Participants in both studies were monitored for at least four weeks after the 14-day treatment.^[2] The primary endpoint of both studies was the change in depressive symptoms using the total score from the 17-item Hamilton depression rating scale (HAMD-17), measured at day 15.^[2] Participants in the zuranolone groups showed significantly more improvement in their symptoms compared to those in the placebo groups.^[2] The treatment effect was maintained at day 42—four weeks after the last dose of zuranolone.^[2]

Society and culture

Zuranolone is the international nonproprietary name.^[11]

Legal status

Zuranolone was approved by the US Food and Drug Administration (FDA) for the treatment of postpartum depression in August 2023.^[2][12] The FDA granted the application for zuranolone priority review and fast track designations.^[2] Approval of Zurzuvae was granted to Sage Therapeutics, Inc.^[2]

Zuranolone has also been under development for the treatment of major depressive disorder, but the application for this use was given a Complete Response Letter (CRL) by the FDA due to insufficient evidence of effectiveness.^[13]

Research

In a randomized, placebo-controlled phase III 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.^[14]

Other investigational applications include insomnia, bipolar depression, essential tremor, and Parkinson’s disease.^[15][6][16]

syn

PATENT

WO2022020363

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022020363&_cid=P11-LLRZ9A-38538-1

Example 1. Synthesis of 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 (Compound 1).

[00488] To a suspension of K²CO³ (50 mg, 0.36 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol) and 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[ ^]phenanthren-17-yl)ethan-1-one (50 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL H²O and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase preparative HPLC to afford Compound 1 as a white solid (9 mg, 17.4% yield).¹H NMR (500 MHZ, CDCl³) δ (ppm) 7.87 (1H, s), 7.82 (1H, s), 5.02 (1H, AB), 4.2 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dxt), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H, s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS: rt=2.24 min, m/z=410.1 [M+H]⁺.

PAPER

Journal of Medicinal Chemistry (2017), 60(18), 7810-7819

https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00846

Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA_A receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABA_A receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).

3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19- nor-5β-pregnan-20-one (3). Yield: 28 g (49%) as an off-white solid. LC-MS: tR = 1.00 min, m/z = 410 (M + 1). 1 H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.80 (s, 1H), 5.08−4.84 (m, 2H), 2.70−2.55 (m, 1H), 2.25−2.15 (m, 1H), 2.10−2.00 (m, 1H), 1.88−1.59 (m, 7H), 1.53−1.30 (m, 15H), 1.25−1.00 (m, 3H), 0.67 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 13.92 (CH3), 23.20, 24.44, 25.54, 25.78, 26.15 (5 × CH2), 26.69 (CH3), 31.43, 34.61 (2 × CH2), 34.77, 37.71 (2 × CH), 39.26 (CH2), 40.35 (CH), 41.21 (CH2), 41.75 (CH), 45.56 (C), 56.04, 61.24 (2 × CH), 61.78 (CH2), 72.14 (C), 93.25 (C), 113.35 (CN), 136.16, 142.49 (2 × CH), 202.23 (CO). HRMS m/z 410.2803 calcd for C25H36N3O2 + 410.2802

PATENT

WO2014169833

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014169833&_cid=P11-LLRZJ9-40598-1

Synthetic Procedures

The compounds of the invention can be prepared in accordance with methods described in the art (Upasmi et al., J. Med. Chem. 1997, 40:73-84; and Hogenkamp et al., J. Med. Chem. 1997, 40:61- 72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. In some embodiments, compounds described herein can be prepared using methods shown in general Schemes 1-4, comprising a nucleophilic substitution of 19-nor pregnane bromide with a neucleophile. In certain embodiments, the nucleophile reacts with the 19-nor pregnane bromide in the presence of K₂CO₃ in THF.

Synthesis of compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) was hydrogenated with 10 atm hydrogen. After stirring at room temperature for 24h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the crude compound. Recrystallization from acetone gave compound SA-B (42.0 g, yield: 83.4%) as white powder.

¹H NMR: (400 MHz, CDCl3) δ 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), 1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).

Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL anhydrous toluene was added dropwise to the methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide (MAD) (459.19 mmol, 3.0 eq, freshly prepared) solution under N₂ at -78°C. After the addition was completed, the reaction mixture was stirred for 1 hr at -78°C. Then 3.0 M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the above mixture under N₂ at -78°C. Then the reaction mixture was stirred for 3 hr at this temperature. TLC (Petroleum ether/ethyl acetate = 3:1) showed the reaction was completed. Then saturated aqueous NH₄Cl was slowly added dropwise

to the above mixture at -78°C. After the addition was completed, the mixture was filtered, the filter cake was washed with EtOAc, the organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated, purified by flash Chromatography on silica gel (Petroleum ether/ ethyl acetate20:1 to 3:1) to afford compound SA-C (40.2 g, yield: 90.4%) as white powder. ¹H NMR: (400 MHz, CDCl3) δ 2.47-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m, 1H), 0.87 (s, 3H).

Synthesis of compound SA-D. To a solution of PPh₃EtBr (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0°C. After the addition was completed, the reaction mixture was stirred for 1 h 60 °C, then SA-C (40.0 g, 137.72 mmol) dissolved in THF (300 mL) was added dropwise at 60°C. The reaction mixture was heated to 60 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with Sat. NH₄Cl, extracted with EtOAc (3*500 mL). The combined organic layers were washed with brine, dried and concentrated to give the crude product, which was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 10:1) to afford compound SA-D (38.4 g, yield:92%) as a white powder. ¹H NMR: (400 MHz, CDCl3) δ 5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).

Synthesis of compound SA-E. To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) was added dropwise a solution of BH₃.Me₂S (126 mL, 1.26 mol) under ice-bath. After the addition was completed, the reaction mixture was stirred for 3 h at room temperature (14-20 °C). TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed. The mixture was cooled to 0 °C and 3.0 M aqueous NaOH solution (400 mL) followed by 30% aqueous H₂O₂ (30%, 300 mL) was added. The mixture was stirred for 2 h at room temperature (14-20 °C), and then filtered, extracted with EtOAc (3*500 mL). The combined organic layers were washed with saturated aqueous Na₂S₂O₃, brine, dried over Na₂SO₄ and concentrated in vacuum to give the crude product (43 g , crude) as colorless oil. The crude product was used in the next step without further purification.

Synthesis of compound SA-F. To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) at 0 °C and PCC (53.8 g, 268.32 mmol) was added portion wise. Then the reaction mixture was stirred at room temperature (16-22 °C) for 3 h. TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed, then the reaction mixture was filtered, washed with DCM. The organic phase was washed with saturated aqueous Na₂S₂O₃, brine, dried over Na₂SO₄ and concentrated in vacuum to give the crude product. The crude product was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 8:1) to afford compound SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. ¹H NMR (SA-F): (400 MHz, CDCl3) δ 2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).

Synthesis of compound SA. To a solution of SA-F (10 g, 31.4 mmol) and aq. HBr (5 drops, 48% in water) in 200 mL of MeOH was added dropwise bromine (5.52 g, 34.54 mmol). The reaction mixture was stirred at 17 °C for 1.5 h. The resulting solution was quenched with saturated aqueous NaHCO₃ at 0°C and extracted with EtOAc (150 mLx2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluted with (PE: EA=15:1 to 6:1) to afford compound SA (9.5 g, yield: 76.14%) as a white solid. LC/MS: rt 5.4 mm ; m/z 379.0, 381.1, 396.1.

To a suspension of K₂CO₃ (50 mg, 0.36mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol ) and SA (50 mg,0.12 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H₂O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (9mg, 17.4%). ¹H NMR (500 MHz, CDCl₃), δ (ppm) 7.87 (1H, s),

7.82 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dXt), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H, s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS: rt = 2.24 mm, m/z = 410.1 [M+H]⁺.

PATENT

WO2020150210

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References

External links

• Clinical trial number NCT04442503 for “A Study to Evaluate the Efficacy and Safety of SAGE-217 in Participants With Severe Postpartum Depression (PPD)” at ClinicalTrials.gov
• Clinical trial number NCT02978326 for “A Study to Evaluate SAGE-217 in Participants With Severe Postpartum Depression” at ClinicalTrials.gov

/////////Zuranolone, FDA 2023, APPROVALS 2023, Zurzuvae, postpartum depression , SAGE 217, SAGE-217, SAGE217

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