NV-5138

NV-5138[2] 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] 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]

NV-5138
Clinical data
Routes of
administration		By mouth[1]
Drug classSestrin2 modulator; mTORC1 activator
Identifiers
IUPAC name
  • (2S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC7H13F2NO2
Molar mass181.183 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)(CC(C(=O)O)N)C(F)F
InChI
  • 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

See also

References
  1. 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. "Research programme: mTORC1 modulators - Navitor Pharmaceuticals". Adis Insight. Springer Nature Switzerland AG.
  4. 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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