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 (March 2019). "Discovery of NV-5138, the first selective Brain mTORC1 activator". Scientific Reports. 9 (1): 4107. doi:10.1038/s41598-019-40693-5. ISSN 2045-2322. PMC 6412019. PMID 30858438.
  3. "Research programme: mTORC1 modulators - Navitor Pharmaceuticals - AdisInsight". adisinsight.springer.com.
  4. Duman, R., Kato, T., Liu, R. J., Duman, C., Terwilliger, R., Vlasuk, G., ... & Sajah, E. (2017, November). Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling. In Neuropsychopharmacology (Vol. 43, pp. S195-S195). Macmillan Building, 4 Crinan St, London N1 9Xw, England: Nature Publishing Group. https://www.nature.com/articles/npp2017264.pdf
  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. doi:10.1126/science.aab2674. PMC 4698017. PMID 26449471.
  6. https://www.biospace.com/article/releases/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/


This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.