Soticlestat | CAS# 1429505-03-2 | Hydroxylase inhibitor

MedKoo Cat#: 572148 | Name: Soticlestat

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Soticlestat, also known as TAK 935 and OV935, is a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), with the potential to reduce seizure susceptibility and improve seizure control. Soticlestat modifies acute seizure burden and chronic epilepsy-related behavioral deficits following Theiler's virus infection in mice. Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a+/- mice.

Chemical Structure

Soticlestat

CAS#1429505-03-2

Theoretical Analysis

MedKoo Cat#: 572148

Name: Soticlestat

CAS#: 1429505-03-2

Chemical Formula: C23H23N3O2

Exact Mass: 373.1790

Molecular Weight: 373.46

Elemental Analysis: C, 73.97; H, 6.21; N, 11.25; O, 8.57

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 250.00	2 Weeks
10mg	USD 450.00	2 Weeks

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Synonym

Soticlestat; TAK-935; TAK935; TAK 935; OV935; OV-935; OV 935;

IUPAC/Chemical Name

(4-benzyl-4-hydroxypiperidin-1-yl)([2,4'-bipyridin]-3-yl)methanone

InChi Key

XKUZMIUSBMCVPP-UHFFFAOYSA-N

InChi Code

InChI=1S/C23H23N3O2/c27-22(20-7-4-12-25-21(20)19-8-13-24-14-9-19)26-15-10-23(28,11-16-26)17-18-5-2-1-3-6-18/h1-9,12-14,28H,10-11,15-17H2

SMILES Code

O=C(N1CCC(O)(CC2=CC=CC=C2)CC1)C3=CC=CN=C3C4=CC=NC=C4

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

CH24H is predominantly expressed in the brain, where it converts cholesterol into 24S-hydroxycholesterol (24HC) to adjust the homeostatic balance of brain cholesterol. 24HC is a positive allosteric modulator of the NMDA receptor and modulates glutamatergic signaling associated with epilepsy. Glutamate is one of the main neurotransmitters in the brain and has been shown to play a role in the initiation and spread of seizure activity. Recent literature indicates that CH24H is involved in over-activation of the glutamatergic pathway through modulation of the NMDA channel and that increased expression of CH24H can disrupt the reuptake of glutamate by astrocytes, resulting in epileptogenesis and neurotoxicity. Inhibition of CH24H by soticlestat reduces the neuronal levels of 24HC and may improve excitatory/inhibitory balance of NMDA channel activit

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Soticlestat is a CH24H inhibitor.

In vitro activity:

To be determined

In vivo activity:

Soticlestat may have therapeutic potential for epilepsy treatment. In a murine model of epilepsy, soticlestat delayed the onset of epilepsy and decreased the number of ensuing seizures by about 3-fold compared to vehicle-treated mice. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells. Reference: Neurobiol Dis. 2022 Oct 15;173:105835. https://pubmed.ncbi.nlm.nih.gov/35932989/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	100.0	267.77

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 373.46 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Salamone A, Terrone G, Di Sapia R, Balosso S, Ravizza T, Beltrame L, Craparotta I, Mannarino L, Cominesi SR, Rizzi M, Pauletti A, Marchini S, Porcu L, Zimmer TS, Aronica E, During M, Abrahams B, Kondo S, Nishi T, Vezzani A. Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy. Neurobiol Dis. 2022 Oct 15;173:105835. doi: 10.1016/j.nbd.2022.105835. Epub 2022 Aug 3. PMID: 35932989. 2. Hawkins NA, Jurado M, Thaxton TT, Duarte SE, Barse L, Tatsukawa T, Yamakawa K, Nishi T, Kondo S, Miyamoto M, Abrahams BS, During MJ, Kearney JA. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice. Epilepsia. 2021 Nov;62(11):2845-2857. doi: 10.1111/epi.17062. Epub 2021 Sep 12. PMID: 34510432; PMCID: PMC9291096.

In vitro protocol:

To be determined

In vivo protocol:

1: Ratcliffe S, Arkilo D, Asgharnejad M, Bhattacharya S, Harden RN. Randomized Controlled Study to Evaluate the Efficacy and Safety of Soticlestat as Adjunctive Therapy in Adults with Complex Regional Pain Syndrome. Pain Med. 2022 Dec 20:pnac198. doi: 10.1093/pm/pnac198. Epub ahead of print. PMID: 36538782. 2: He Z, Li Y, Zhao X, Li B. Dravet syndrome: Advances in etiology, clinical presentation, and treatment. Epilepsy Res. 2022 Dec;188:107041. doi: 10.1016/j.eplepsyres.2022.107041. Epub 2022 Oct 29. PMID: 36368227. 3: Barker-Haliski M, Nishi T, White HS. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, modifies acute seizure burden and chronic epilepsy- related behavioral deficits following Theiler's virus infection in mice. Neuropharmacology. 2023 Jan 1;222:109310. doi: 10.1016/j.neuropharm.2022.109310. Epub 2022 Oct 29. PMID: 36341806. 4: Wu J, Zhang L, Zhou X, Wang J, Zheng X, Hu H, Wu D. Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis. Front Pharmacol. 2022 Aug 31;13:980937. doi: 10.3389/fphar.2022.980937. PMID: 36120377; PMCID: PMC9471196. 5: Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Perucca P, Tomson T, White HS. Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): II. Drugs in more advanced clinical development. Epilepsia. 2022 Nov;63(11):2883-2910. doi: 10.1111/epi.17376. Epub 2022 Aug 11. PMID: 35950617. 6: Salamone A, Terrone G, Di Sapia R, Balosso S, Ravizza T, Beltrame L, Craparotta I, Mannarino L, Cominesi SR, Rizzi M, Pauletti A, Marchini S, Porcu L, Zimmer TS, Aronica E, During M, Abrahams B, Kondo S, Nishi T, Vezzani A. Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy. Neurobiol Dis. 2022 Oct 15;173:105835. doi: 10.1016/j.nbd.2022.105835. Epub 2022 Aug 3. PMID: 35932989. 7: Ikeda S, Kajita Y, Miyamoto M, Matsumiya K, Ishii T, Nishi T, Gay SC, Lane W, Constantinescu CC, Alagille D, Papin C, Tamagnan G, Kuroita T, Koike T. Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H). Eur J Med Chem. 2022 Oct 5;240:114612. doi: 10.1016/j.ejmech.2022.114612. Epub 2022 Jul 14. PMID: 35863274. 8: Hahn CD, Jiang Y, Villanueva V, Zolnowska M, Arkilo D, Hsiao S, Asgharnejad M, Dlugos D. A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome (ELEKTRA). Epilepsia. 2022 Oct;63(10):2671-2683. doi: 10.1111/epi.17367. Epub 2022 Aug 4. PMID: 35841234; PMCID: PMC9804149. 9: Pong AW, Ross J, Tyrlikova I, Giermek AJ, Kohli MP, Khan YA, Salgado RD, Klein P. Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials. Expert Opin Emerg Drugs. 2022 Mar;27(1):75-90. doi: 10.1080/14728214.2022.2059464. Epub 2022 Apr 1. PMID: 35341431. 10: Nishi T, Metcalf CS, Fujimoto S, Hasegawa S, Miyamoto M, Sunahara E, Watanabe S, Kondo S, White HS. Anticonvulsive properties of soticlestat, a novel cholesterol 24-hydroxylase inhibitor. Epilepsia. 2022 Jun;63(6):1580-1590. doi: 10.1111/epi.17232. Epub 2022 Mar 30. PMID: 35316533; PMCID: PMC9311151. 11: Guo Y, Shah A, Oh E, Chowdhury SK, Zhu X. Determination of Acyl-, O-, and N-Glucuronide Using Chemical Derivatization Coupled with Liquid Chromatography-High-Resolution Mass Spectrometry. Drug Metab Dispos. 2022 May;50(5):716-724. doi: 10.1124/dmd.122.000832. Epub 2022 Mar 3. PMID: 35241454. 12: Kajita Y, Ikeda S, Yoshikawa M, Fukuda H, Watanabe E, Yano J, Lane W, Miyamoto M, Ishii T, Nishi T, Koike T. Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors. J Med Chem. 2022 Feb 24;65(4):3343-3358. doi: 10.1021/acs.jmedchem.1c01898. Epub 2022 Feb 15. PMID: 35166541. 13: Wang S, Chen G, Merlo Pich E, Affinito J, Cwik M, Faessel HM. Pharmacokinetics, pharmacodynamics and safety assessment of multiple doses of soticlestat in healthy volunteers. Br J Clin Pharmacol. 2022 Jun;88(6):2899-2908. doi: 10.1111/bcp.15225. Epub 2022 Jan 31. PMID: 35001412; PMCID: PMC9305210. 14: Koike T, Constantinescu CC, Ikeda S, Nishi T, Sunahara E, Miyamoto M, Cole P, Barret O, Alagille D, Papin C, Morley T, Fowles K, Seibyl J, Tamagnan G, Kuroita T. Preclinical characterization of [18F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase. Eur J Nucl Med Mol Imaging. 2022 Mar;49(4):1148-1156. doi: 10.1007/s00259-021-05565-z. Epub 2021 Oct 15. PMID: 34651220; PMCID: PMC8921165. 15: Hawkins NA, Jurado M, Thaxton TT, Duarte SE, Barse L, Tatsukawa T, Yamakawa K, Nishi T, Kondo S, Miyamoto M, Abrahams BS, During MJ, Kearney JA. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice. Epilepsia. 2021 Nov;62(11):2845-2857. doi: 10.1111/epi.17062. Epub 2021 Sep 12. PMID: 34510432; PMCID: PMC9291096. 16: Koike T, Yoshikawa M, Ando HK, Farnaby W, Nishi T, Watanabe E, Yano J, Miyamoto M, Kondo S, Ishii T, Kuroita T. Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H). J Med Chem. 2021 Aug 26;64(16):12228-12244. doi: 10.1021/acs.jmedchem.1c00864. Epub 2021 Aug 13. PMID: 34387987. 17: Halford JJ, Sperling MR, Arkilo D, Asgharnejad M, Zinger C, Xu R, During M, French JA. A phase 1b/2a study of soticlestat as adjunctive therapy in participants with developmental and/or epileptic encephalopathies. Epilepsy Res. 2021 Aug;174:106646. doi: 10.1016/j.eplepsyres.2021.106646. Epub 2021 Apr 22. PMID: 33940389. 18: Wang S, Chen G, Merlo Pich E, Affinito J, Cwik M, Faessel H. Safety, tolerability, pharmacokinetics, pharmacodynamics, bioavailability and food effect of single doses of soticlestat in healthy subjects. Br J Clin Pharmacol. 2021 Nov;87(11):4354-4365. doi: 10.1111/bcp.14854. Epub 2021 May 5. PMID: 33837574; PMCID: PMC8597018. 19: Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Lennox- Gastaut Syndrome: Current and Future Strategies. CNS Drugs. 2021 Jan;35(1):61-83. doi: 10.1007/s40263-020-00784-8. Epub 2021 Jan 21. PMID: 33479851; PMCID: PMC7873005. 20: Miziak B, Czuczwar S. Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome. Expert Opin Drug Discov. 2021 May;16(5):579-593. doi: 10.1080/17460441.2021.1857722. Epub 2020 Dec 17. PMID: 33275464.