Direclidine

CAS 1803346-98-6

MF C19H30N4O2 MW346.5 g/mol

ethyl 2-[4-(2-methylpyrazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

6-Azaspiro[3.4]octane-6-carboxylic acid, 2-[4-(1-methyl-1H-pyrazol-5-yl)-1-piperidinyl]-, ethyl ester, cis-

ethyl (2r,4s)-2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate
muscarinic M4 receptor positive allosteric modulator, TXB4V44U24, NBI-1117568, NBI 1117568

Direclidine (INNTooltip International Nonproprietary Name;^[2] developmental code names NBI-1117568, HTL-0016878)^[1] is an investigational antipsychotic drug for schizophrenia^[3] that was out-licensed from Nxera Pharma to Neurocrine Biosciences, a United States-based pharmaceutical company.^[4][1][5] It is an oral small molecule.^[6][7]

Direclidine (NBI-1117568) is an investigational, oral drug in Phase 3 trials for schizophrenia, developed by Neurocrine Biosciences, working as a selective M4 muscarinic receptor agonist to treat psychosis by modulating dopamine indirectly. It’s an innovative small molecule with potential for neuropsychiatric disorders, showing promise in early trials and aiming to offer a new treatment approach beyond traditional antipsychotics. 

Key aspects of Direclidine:

• Drug Class: Small molecule, muscarinic M4 receptor agonist, antipsychotic.
• Mechanism: Acts as a selective agonist for the M4 receptor, which indirectly helps improve dopamine levels, targeting schizophrenia symptoms.
• Developer: Originally from Nxera Pharma, licensed to Neurocrine Biosciences.
• Status: In Phase 3 clinical trials for schizophrenia.
• Significance: Offers a novel mechanism for treating schizophrenia, potentially with fewer side effects than current treatments.
• Other Uses: Also being explored for bipolar mania and other neuropsychiatric conditions. 

Development Timeline & Data:

• Positive Phase 2 data was announced in August 2024, showing promise for its use in schizophrenia.
• Topline data from ongoing Phase 3 studies is expected around 2027. 

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015118342&_cid=P20-MKJ4D7-04370-1

Typical procedure for the preparation of piperidines via sodium triacetoxyborohydride reductive amination, Boc-deprotection and ethylcarbamate formation as exemplified by the preparation of Example 1 -7, ethyl 2-[4-(1 -methyl-1 H-imidazol-2-yl)piperidin-1 -yl]-6-aza s p i ro [3.4] octa n e -6 -ca rb oxy late

Example 1-7

4-(1 -Methylimidazol-2-yl)piperidine hydrochloride (0.244 g, 1 .21 mmol) and 6-Boc-2-oxo-6-azaspiro[3,4]octane (0.273 g, 1 .21 mmol) were dissolved in DCM (10 mL) at rt and titanium isopropoxide (0.4 mL, 2.42 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was cooled to -5 °C, then STAB (0.513 g, 2.42 mmol) and acetic acid (27 pL, 480 pmol) were added and the reaction mixture was stirred overnight under nitrogen while warming to rt. The reaction mixture was quenched with the addition of NaHC0₃ (sat aq.) (10 mL) and diluted with DCM then filtered through a pad of celite. The layers were separated and the aqueous layer was extracted with DCM. The combined DCM layers were washed with brine, then dried over MgS0₄. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25g , 40-63 μΠΊ, 60 A, 50 mL per min, gradient 1 % to 10% MeOH in DCM]) to give an inseparable mixture of isomers of terf-butyl 2-[4-(1 -methyl-1 H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate (0.330 g, 72%) as a yellow gum.

LCMS (Method A): m/z 374 (M+H)⁺ (ES*), at 1.68 min, UV inactive.

Terf-butyl 2-[4-(1-methyl-1 H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate (0.326 g, 0.87 mmol) was dissolved in 4 M hydrogen chloride in dioxane (1 .2 mL, 5.2 mmol). The reaction mixture was stirred at rt for 18 h. The volatiles were then removed in vacuo and the residue dissolved DCM (17 mL) and triethylamine (0.49 mL, 3.49 mmol). Ethyl chloroformate (125 μί, 1.31 mmol) was added dropwise and the solution stirred at rt for 18 h. The mixture was then poured into NaHC0₃ (aq) (75 mL) and DCM (75 mL), extracted (2 x 75 mL) , and the combined DCM extracts washed with brine (20 mL) then dried over MgSO*. After concentration, the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μΐη, 60 A, 50 mL per min, gradient 1 % to 10% MeOH in DCM]) to provide ethyl 2-[4-(1 -methyl-1 H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate as a brown oil as a mixture of diastereomers (0.25 g, 83%). Preparative HPLC was used to separate the diastereomers, using a Phenomenex Gemini-N C18 column, 150 x 21 mm, eluting with 38 to 48% MeCN/H₂0 at 18 mL/min and collecting fractions by monitoring at 218 nm to give ethyl 2-[4-(1 -methyl-1 H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate, Example 1-7 Isomer 1 , (0.044 g, 15%) as a colourless oil and ethyl 2-[4-(1 -methyl-1 /-/-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate, Example 1 -7 Isomer 2, (0.031 g, 10%) as a colourless oil. The data for Isomer 2 are in Table 3

PAT

• Pharmaceutical compoundsPublication Number: EP-4413985-A2Priority Date: 2014-02-06
• BICYCLIC AZA COMPOUNDS AS MUSCARINIC RECEPTOR AGONISTSPublication Number: FI-3406609-T3Priority Date: 2014-02-06Grant Date: 2024-09-10
• Bicyclic aza compounds as muscarinic receptor agonistsPublication Number: EP-3406609-B1Priority Date: 2014-02-06Grant Date: 2024-06-26
• Bicyclic aza compounds as muscarinic m1 receptor agonists.Publication Number: WO-2015118342-A1Priority Date: 2014-02-06
• Bicyclic aza compounds as muscarinic m1 receptor and/or m4 receptor agonistsPublication Number: US-2018179184-A1Priority Date: 2014-02-06
• Bicyclic aza compounds as muscarinic m1 receptor and/or m4 receptor agonistsPublication Number: US-2017240530-A1Priority Date: 2014-02-06
• Bicyclic aza compounds as muscarinic m1 receptor and/or m4 receptorPublication Number: US-2020325118-A1Priority Date: 2014-02-06
• Bicyclic aza compounds as muscarinic receptor agonistsPublication Number: ES-2986327-T3Priority Date: 2014-02-06Grant Date: 2024-11-11

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Overview

It is a selective muscarinic acetylcholine M₄ receptor agonist that indirectly modulates dopamine as the basis for its putative improvement of schizophrenia.^[6] In April 2016, the compound was out-licensed from Nxera Pharma to Allergan, an Irish pharmaceutical company, as part of Nxera’s wider muscarinic agonist portfokio. By September 2017, it had advanced to Phase I clinical trial for the indication of “neuropsychiatric symptoms associated with Alzheimer’s disease and other dementias”^[8] Following Allergan’s acquisition by AbbVie, the license was returned to Nxera in January 2021.^[9] In November 2021, the compound was newly out-licensed to Neurocrine Biosciences, a U.S. pharmaceutical company.^[5] It has been under development as a treatment for schizophrenia, and is currently in Phase III clinical trials.^[10][11]

History

• 2016
  • April: The rights to develop Nxera Pharma’s muscarinic agonist portfolio, including NBI-1117568 were transferred to Allergan.^[9]
• 2017
  • September: Allergan initiated Phase I clinical trials for NBI-1117568 to treat “neurobehavioral symptoms related to Alzheimer’s disease and other conditions.”^[8]
• 2021
  • January: Allergan returned the rights to its muscarinic agonist portfolio, including, NBI-1117568 to Nxera Pharma.^[9]
  • November: The rights for the muscarinic agonist portfolio were then transferred to Neurocrine Biosciences, which took over the development of NBI-1117568.^[5]
• 2022
  • October: Phase II clinical trial of NBI-1117568 for the treatment of adults with schizophrenia was initiated.^[12]
• 2024
  • April: Neurocrine Biosciences announced that NBI-1117568 had met the requirements of long-term preclinical toxicity tests.^[6]
  • August: Neurocrine Biosciences released the results of the Phase II clinical trial.^[13][11]
• 2025
  • May: Neurocrine Biosciences initiated a Phase III registrational program for NBI-1117568 for the treatment of adults with schizophrenia.^[14]

Clinical trials

Phase II clinical trial

The Phase II clinical trial was conducted in 15 sites across the U.S. with 200 adult patients diagnosed with schizophrenia.^[15] The primary endpoint was assessed by the change in the total score of the Positive and Negative Syndrome Scale (PANSS) after six weeks of treatment. The 20 mg once-daily group showed a statistically significant improvement of 7.5 points compared to the placebo group (improvement of 18.2 points from baseline, p = 0.011, effect size = 0.61).^[16] However, the 40 mg once-daily group, 60 mg once-daily group, and 30 mg twice-daily group did not show statistically significant differences compared to the placebo group (p-values: 40 mg group: 0.282, 60 mg group: 0.189, 30 mg twice-daily group: 0.090).^[16]

Market reaction to phase II clinical trial

With a PANSS improvement of 7.5, NBI-111758 lagged behind xanomeline/trospium (KarXT) (Karuna Therapeutics) with 8.4 and emraclidine (Cerevel Therapeutics) with 12.7, both of which were in clinical trials at the same time. Moreover, the lack of dose-dependency led to disappointment in the stock market.^[17] Neurocrine Biosciences’ share price dropped 19% on the day following the announcement of the Phase II clinical trial results.^[18]

References

1.  “Delving into the Latest Updates on Direclidine with Synapse”. Synapse. 30 June 2025. Retrieved 27 July 2025.
2.  https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl133.pdf ^{[bare URL PDF]}
3.  Ye N, Wang Q, Li Y, Zhen X (March 2025). “Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities”. Medicinal Research Reviews. 45 (2): 755–787. doi:10.1002/med.22086. PMID 39300769.
4.  “HTL 0016878”. AdisInsight. 2 September 2024. Retrieved 21 October 2024.
5.  “ニューロクライン社との統合失調症およびその他の精神神経疾患を対象とした新規ムスカリン受容体作動薬に関するライセンス契約締結のお知らせ” [Announcement of License Agreement with Neurocrine for Novel Muscarinic Receptor Agonist for Schizophrenia and Other Neuropsychiatric Disorders] (in Japanese). PR TIMES. 2021-11-22. Retrieved 2024-09-17.
6.  “ネクセラファーマ株価6.5%高 薬候補で毒性試験成功 – 日本経済新聞” [NexThera Pharma shares rise 6.5% as drug candidate passes toxicity test – Nikkei]. 日本経済新聞 電子版 (Nikkei Electronic Edition) (in Japanese). 日本経済新聞社 (Nikkei Inc.). 2024-04-17. Retrieved 2024-09-17.
7.  “当社提携先のニューロクライン社が、統合失調症を対象にしたNBI-1117568の第II相臨床試験の開始を発表［そーせいグループ］ | NIKKEI COMPASS – 日本経済新聞” [Our partner Neurocrine, Inc. announces initiation of Phase II clinical trial of NBI-1117568 for schizophrenia [Sosei Group] | NIKKEI COMPASS – Nikkei Newspaper]. 日経コンパス (Nikkei Compass) (in Japanese). 日本経済新聞社 (Nikkei Inc.). 2022-10-28. Retrieved 2024-09-17.
8.  “アルツハイマー病等の主要症状の治療薬として開発中の新薬候補、 選択的ムスカリンM4受容体作動薬の第I相臨床試験で最初の被験者への投与を実施” [First subjects dosed in Phase I clinical trial of selective muscarinic M4 receptor agonist, a potential new drug candidate for treating major symptoms of Alzheimer’s disease] (PDF) (in Japanese). ネクセラファーマ（旧そーせいグループ株式会社）. 2017-09-01. Retrieved 2024-09-17.
9.  “ムスカリン作動薬プログラムのグローバルな研究開発権・販売権が返還” [Global R&D and commercial rights to muscarinic agonist program returned]. プレスリリース・ニュースリリース配信シェアNo.1｜PR TIMES (in Japanese). PR Times. 2021-01-05. Retrieved 2024-09-17.
10.  日経バイオテクONLINE (2024-09-02). “ネクセラファーマ、統合失調症治療薬候補 NBI-1117568の第II相臨床試験の良好な結果によりニューロクライン社より35百万米ドルのマイルストンを受領” [Nexella Pharma Receives $35 Million Milestone Payment from Neurocrine Following Positive Results of Phase II Clinical Trial of NBI-1117568, a Potential Treatment for Schizophrenia]. 日経バイオテクONLINE (in Japanese). 日本経済新聞社. Retrieved 2024-09-17.
11.  “ネクセラ—大幅反落、ニューロクラインの株価下落に追随売り | 個別株 – 株探ニュース” [Nexella – Sharp decline, selling follows fall in Neurocrine stock price | Individual stocks – Kabutan News]. kabutan.jp (in Japanese). MINKABU THE INFONOID, Inc. 2024-08-29. Retrieved 2024-09-17.
12.  “当社提携先のニューロクライン社が、統合失調症を対象にしたNBI-1117568の第Ⅱ相臨床試験の開始を発表” [Our Partner Neurocrine Announces Initiation of Phase 2 Clinical Trial of NBI-1117568 for Schizophrenia]. プレスリリース・ニュースリリース配信シェアNo.1｜PR TIMES (in Japanese). PR TIMES. 2022-10-28. Retrieved 2024-09-17.
13.  日経バイオテク (Nikkei Biotech) ONLINE (2024-09-02). “ネクセラファーマ、統合失調症治療薬候補 NBI-1117568の第II相臨床試験の良好な結果によりニューロクライン社より35百万米ドルのマイルストンを受領” [Nexella Pharma Receives $35 Million Milestone Payment from Neurocrine Following Positive Results of Phase II Clinical Trial of NBI-1117568, a Potential Treatment for Schizophrenia]. 日経バイオテクONLINE (in Japanese). 日本経済新聞社. Retrieved 2024-09-17.
14.  “ネクセラファーマの統合失調症薬、最終治験を開始”. 日本経済新聞. 日本経済新聞社. 2025-05-01. Retrieved 2025-05-02.
15.  “Neurocrine Biosciences Initiates Phase 2 Clinical Study Evaluating NBI-1117568 in Adults with Schizophrenia”. ニューロクライン. 2022-10-27. Retrieved 2024-09-17.
16.  “ネクセラファーマ[4565]：ニューロクライン社との提携プログラムである統合失調症治療薬候補NBI-1117568の第2相臨床試験で良好な結果 2024年8月28日(適時開示) ：日経会社情報DIGITAL：日本経済新聞” [Nexella Pharma [4565]: Positive results in Phase 2 clinical trial of NBI-1117568, a candidate for the treatment of schizophrenia, a collaboration program with Neurocrine, Inc. August 28, 2024 (timely disclosure) : Nikkei Company Information DIGITAL: Nikkei Shimbun]. 日本経済新聞 電子版 (in Japanese). 日本経済新聞社. Retrieved 2024-09-17.
17.  “Nxera Pharma Official IR Blog 「ニューロクライン社から35百万米ドルのマイルストン受領」” [Received $35 million milestone payment from Neurocrine]. soseiheptares.blogspot.com. ネクセラファーマ. 2024-09-02. Retrieved 2024-09-19.
18.  “Neurocrine Stock Down 19% on Mixed Schizophrenia Study Results”. Zacks Investment Research. Zacks Investment. 2024-08-29. Retrieved 2024-09-17.

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