Chemistry:NV-5138
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| Routes of administration | By mouth[1] |
| Drug class | Sestrin2 modulator; mTORC1 activator |
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| Formula | C7H13F2NO2 |
| Molar mass | 181.183 g·mol−1 |
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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]
See also
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Research 7: 659. 2018. doi:10.12688/f1000research.14344.1. PMID 29899972.
- ↑ "Discovery of NV-5138, the first selective Brain mTORC1 activator". Scientific Reports 9 (1): 4107. March 2019. doi:10.1038/s41598-019-40693-5. PMID 30858438. Bibcode: 2019NatSR...9.4107S.
- ↑ 3.0 3.1 "Research programme: mTORC1 modulators - Navitor Pharmaceuticals". Adis Insight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800040858.
- ↑ 4.0 4.1 4.2 4.3 4.4 "Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling". Neuropsychopharmacology 42 (1): S111–S293. November 2017. doi:10.1038/npp.2017.264. ACNP 56th Annual Meeting: Poster Session I, December 4, 2017.
- ↑ "Sestrin2 is a leucine sensor for the mTORC1 pathway". Science 351 (6268): 43–48. January 2016. doi:10.1126/science.aab2674. PMID 26449471. Bibcode: 2016Sci...351...43W.
- ↑ "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". 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/.
- ↑ "Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status". CNS Drugs 35 (5): 527–543. May 2021. doi:10.1007/s40263-021-00816-x. PMID 33904154.
- ↑ Clinical trial number NCT05066672 for "Phase 2 Study of Efficacy and Safety of NV-5138 in Adults With Treatment Resistant Depression." at ClinicalTrials.gov
External links
- NV-5138 - AdisInsight
- NV-5138 for Treatment-Resistant Depression - Navitor Pharmaceuticals
- Sestrin2 modulator NV-5138, shows ketamine-like rapid antidepressant effects via direct activation of mTORC1 signaling - Navitor Pharmaceuticals
- Navitor Pharmaceuticals to Develop NV-5138, a Specific Activator of mTORC1 for Treatment-Resistant Depression, Based on Promising Data Presented at Society for Neuroscience 2017 - BusinessWire
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