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] As of November 2019, NV-5138 has 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]

NV-5138
Clinical data
Routes of
administration		By mouth[1]
Drug classSestrin2 modulator; mTORC1 activator
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC7H13F2NO2
Molar mass181.183 g·mol−1
3D model (JSmol)

See also

References
  1. Duman RS (2018). "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Res. 7: 659. doi:10.12688/f1000research.14344.1. PMC 5968361. PMID 29899972.
  2. Sengupta, Shomit; Giaime, Emilie; Narayan, Sridhar; Hahm, Seung; Howell, Jessica; O’Neill, David; Vlasuk, George P.; Saiah, Eddine (11 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 - AdisInsight". adisinsight.springer.com.
  4. "Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling" in "ACNP 56th Annual Meeting: Poster Session I, December 4, 2017". Neuropsychopharmacology. 42 (1): S111–S293. November 2017. doi:10.1038/npp.2017.264. PMC 5719065.
  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): 43–8. 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".
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