Wikipedia

NV-5138

NV-5138,[2] also known as SPN-820, is an orally and centrally active small-molecule drug which is under development by Navitor Pharmaceuticals for the treatment of major depressive disorder (MDD).[3][1][4] It directly and selectively activates the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway by binding to and modulating sestrin2, a leucine amino acid sensor and upstream regulatory pathway.[1][4][5]

NV-5138
Clinical data
Routes of
administration		By mouth[1]
Drug classSestrin2 modulator; mTORC1 activator
Identifiers
  • (2S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC7H13F2NO2
Molar mass181.183 g·mol−1
3D model (JSmol)
  • CC(C)(CC(C(=O)O)N)C(F)F
  • InChI=1S/C7H13F2NO2/c1-7(2,6(8)9)3-4(10)5(11)12/h4,6H,3,10H2,1-2H3,(H,11,12)/t4-/m0/s1
  • Key:HRFIMCJTDKEPPV-BYPYZUCNSA-N

The mTORC1 pathway is the same signaling pathway that the NMDA receptor antagonist ketamine activates in the medial prefrontal cortex (mPFC) to mediate its rapid-acting antidepressant effects.[1][4] A single oral dose of NV-5138 has been found to increase mTORC1 signaling and produce synaptogenesis in the mPFC and to induce rapid antidepressant effects in multiple animal models of depression.[1][4] Like those of ketamine, these actions require the signaling of brain-derived neurotrophic factor (BDNF).[1] The antidepressant effects following a single dose of NV-5138 are long-lasting, with a duration of up to 7 days, and are similar to those of ketamine.[1][4]

Based on these promising preclinical findings, efforts are underway to assess NV-5138 in clinical trials with human subjects.[1] By November 2019, NV-5138 had completed three phase I studies for the treatment of MDD.[3] In these studies, preliminary evidence of efficacy, tolerability, safety, and pharmacokinetics was observed,[6] and as of 2021 it was into Phase II trials.[7][8]

See also

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References

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  1. ^ a b c d e f g h Duman RS (2018). "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Research. 7: 659. doi:10.12688/f1000research.14344.1. PMC 5968361. PMID 29899972.
  2. ^ Sengupta S, Giaime E, Narayan S, Hahm S, Howell J, O'Neill D, et al. (March 2019). "Discovery of NV-5138, the first selective Brain mTORC1 activator". Scientific Reports. 9 (1): 4107. Bibcode:2019NatSR...9.4107S. doi:10.1038/s41598-019-40693-5. PMC 6412019. PMID 30858438.
  3. ^ a b "Research programme: mTORC1 modulators - Navitor Pharmaceuticals". Adis Insight. Springer Nature Switzerland AG.
  4. ^ a b c d e Duman R, Kato T, Liu RJ, Duman C, Terwilliger R, Vlasuk G, Hahm S, Sajah E (November 2017). "Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling". Neuropsychopharmacology. 42 (1): S111–S293. doi:10.1038/npp.2017.264. PMC 5719065. ACNP 56th Annual Meeting: Poster Session I, December 4, 2017.
  5. ^ Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, Sabatini DM (January 2016). "Sestrin2 is a leucine sensor for the mTORC1 pathway". Science. 351 (6268): 43–48. Bibcode:2016Sci...351...43W. doi:10.1126/science.aab2674. PMC 4698017. PMID 26449471.
  6. ^ "Navitor's Three Phase 1 Studies for NV-5138 Show Antidepressant Effects and Biomarker Impact, Supporting Further Development of Direct Activator of mTORC1 in Depression".
  7. ^ Henter ID, Park LT, Zarate CA (May 2021). "Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status". CNS Drugs. 35 (5): 527–543. doi:10.1007/s40263-021-00816-x. PMC 8201267. PMID 33904154.
  8. ^ Clinical trial number NCT05066672 for "Phase 2 Study of Efficacy and Safety of NV-5138 in Adults With Treatment Resistant Depression." at ClinicalTrials.gov
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