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Danavorexton, TAK 925



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Danavorexton Structure.svg

Danavorexton,  TAK 925


  • Molecular FormulaC21H32N2O5S
  • Average mass424.554 Da

1-Piperidinecarboxylic acid, 3-[(methylsulfonyl)amino]-2-[[(cis-4-phenylcyclohexyl)oxy]methyl]-, methyl ester, (2R,3S)-

Methyl (2R,3S)-3-[(methylsulfonyl)amino]-2-[[(cis-4-phenylcyclohexyl)oxy]methyl]-1-piperidinecarboxylate

  • OriginatorTakeda
  • ClassCyclohexanes; Esters; Ethers; Piperidines; Sleep disorder therapies; Small molecules; Sulfonamides
  • Mechanism of ActionOrexin receptor type 2 agonists
  • Orphan Drug StatusYes – Narcolepsy
  • Phase IHypersomnia; Narcolepsy; Respiration disorders; Sleep apnoea syndrome
  • 01 Jun 2022Takeda Pharmaceuticals completes a phase I clinical trials in Respiratory disorder (In adults) in Netherlands (IV) (ISRCTN63027076)
  • 02 Apr 2022Efficacy and safety data from phase a Ib trial in Hypersomnia presented at the 74th Annual Meeting of the American Academy of Neurology 2022 (AAN-2022)
  • 10 Mar 2022Phase-I clinical trials in Sleep apnoea syndrome in Australia (IV) (NCT05180890)

Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist.[1] It is a small-molecule compound and is administered intravenously.[1][2] The compound was found to dose-dependently produce wakefulness to a similar degree as modafinil in a phase 1 clinical trial.[1][3] As of March 2021, danavorexton is under development for the treatment of narcolepsyidiopathic hypersomnia, and sleep apnea.[2][1][4] It is related to another orexin receptor agonist known as TAK-994, the development of which was discontinued for safety reasons in October 2021.[1][5]


TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16], was identified through the optimization of compound 2, which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

aReagents and conditions: (a) chiral column separation; (b) RCOCl, Et3N, THF, rt (for 15 and 16); (c) ethyl chlorocarbonate, DIEA, THF, rt (for 17); (d) isocyanatoethane, Et3N, THF, 0 °C−rt (for 18).

Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (16) To a mixture of 14 (58 mg, 0.16 mmol) and Et3N (0.044 mL, 0.32 mmol) in THF (3 mL) was added methyl chlorocarbonate (0.024 mL, 0.32 mmol) at rt. The mixture was stirred at rt overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc, 1:1 to 0:100) to give 16 (64 mg, 0.15 mmol, 95%) as a colorless oil. Crystallization of 16 (1.8 g, 4.1 mmol) from EtOH-H2O gave 16 (1.7 g, 3.9 mmol, 95%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 1.40−1.55 (5H, m), 1.56−1.73 (5H, m), 1.87 (1H, brd, J = 13.2 Hz), 1.96 (1H, brd, J = 13.6 Hz), 2.44−2.57 (1H, m), 2.83 (1H, brs), 2.95 (3H, s), 3.40 (1H, brs), 3.53−3.62 (5H, m), 3.73 (1H, brt, J = 9.7 Hz), 3.84 (1H, brs), 4.47 (1H, brs), 7.15 (1H, brt, J = 7.2 Hz), 7.18 (1H, brs), 7.19 (2H, brd, J = 8.1 Hz), 7.27 (2H, brt, J = 7.4 Hz). 13C NMR (151 MHz, DMSO-d6, the minor rotamer’s signals are marked with an asterisk) δ24.05, 24.39*, 26.00, 26.17*, 27.60*, 27.79, 28.68, 30.15*, 37.54, 38.13*, 39.91, 42.99, 51.01, 52.07, 53.90*, 54.49, 61.48, 61.89*, 71.68, 125.68, 126.51, 128.14, 147.34, 155.27*, 156.08. MS (ESI/APCI) mass calculated for [M + H]+ (C21H33N2O5S) requires m/z 424.6, found m/z 425.2. mp 113 °C. Anal. Calcd for C21H32N2O5S: C, 59.41; H, 7.60; N, 6.60. Found: C, 59.45; H, 7.59; N, 6.55. [α] 20 D +16.3 (c 0.1, CHCl3


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Clinical data
Other namesTAK-925
Routes of
Drug classOrexin receptor agonist
showIUPAC name
CAS Number2114324-48-8
PubChem CID130310079
Chemical and physical data
Molar mass424.56 g·mol−1
3D model (JSmol)Interactive image


  1. Jump up to:a b c d e f Jacobson LH, Hoyer D, de Lecea L (January 2022). “Hypocretins (orexins): The ultimate translational neuropeptides”. J Intern Meddoi:10.1111/joim.13406PMID 35043499.
  2. Jump up to:a b c “Danavorexton – Takeda”Adis Insight. Springer Nature Switzerland AG. Retrieved 7 March 2021.
  3. ^ Evans, R., Hazel, J., Faessel, H., Wu, J., Hang, Y., Alexander, R., … & Hartman, D. (2019). Results of a phase 1, 4-period crossover, placebo-controlled, randomized, single dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-925, a novel orexin 2 receptor agonist, in sleep-deprived healthy adults, utilizing modafinil as an active comparator. Sleep Medicine, 64, S106.
  4. ^ Evans R, Tanaka S, Tanaka S, Touno S, Shimizu K, Sakui S, et al. (December 2019). “A Phase 1 single ascending dose study of a novel orexin 2 receptor agonist, TAK-925, in healthy volunteers (HV) and subjects with narcolepsy type 1 (NT1) to assess safety, tolerability, pharmacokinetics, and pharmacodynamic outcomes”. Sleep Medicine64: S105–S106. doi:10.1016/j.sleep.2019.11.290.
  5. ^ Tong A (6 October 2021). “Takeda flashes red light on ‘breakthrough’ narcolepsy drug after PhII trials turned up mysterious safety signal”Endpoints News.

External links

///////////////Danavorexton,  TAK 925, ORPHAN DRUG, PHASE 1





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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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