Apimostinel
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| Other names | NRX-1074; AGN-241660; Threonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide |
| Routes of administration | By mouth |
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| Formula | C25H37N5O6 |
| Molar mass | 503.600 g·mol−1 |
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Apimostinel (former developmental code name NRX-1074) is a novel antidepressant, acting as a selective partial agonist of an allosteric site of the glycine site of the NMDA receptor complex, which is under investigation by Naurex (recently acquired by Allergan for $560 million in late 2015) for the treatment of major depressive disorder.[1][2][3][4][5] As of 2015, an intravenous formulation of apimostinel is in a phase II clinical trial for MDD,[3][6] and an oral formulation is concurrently in phase I trials for MDD.
Its mechanism of action and effects are similar to those of rapastinel (GLYX-13), which is under development as an adjunctive therapy for treatment-resistant depression also by Naurex. However, apimostinel is 100-fold more potent by weight and, whereas rapastinel must be administered via intravenous injection, is orally-active.[3] Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel. Similarly to rapastinel, apimostinel is an amidated tetrapeptide, and has almost an identical chemical structure to rapastinel, but has been structurally modified via the addition of a benzyl group. The drug has shown rapid antidepressant effects in pre-clinical models of depression.[3] In addition, similarly to rapastinel, it is well-tolerated and lacks the schizophrenia-like psychotomimetic effects of other NMDA receptor antagonists such as ketamine.[3]
Commercial competitors of apimostinel include AV-101 from VistaGen Therapeutics and Cerecor's CERC-301.[8]
See also
References
- ^ Hayley S, Litteljohn D (2013). "Neuroplasticity and the next wave of antidepressant strategies". Front Cell Neurosci. 7: 218. doi:10.3389/fncel.2013.00218. PMC 3834236. PMID 24312008.
Despite the mounting evidence indicating that ketamine has rapid and robust antidepressant properties (and notwithstanding the earlier mentioned preliminary clinical data indicating that long-term, low-dose ketamine may be both tolerable and effective; e.g., Messer et al., 2010), concerns over ketamine's psychotomimetic effects have spurred intensive efforts to develop safer and more tolerable glutamate-based antidepressants. At the vanguard of this movement are the "next generation" NMDA receptor antagonists. Included here are the aminoadamantanes, memantine and amantadine (Sani et al., 2012); the NR2B-selective antagonists, traxoprodil (CP-101,606; Preskorn et al., 2008) and MK-0657 (Ibrahim et al., 2012a); and the low-affinity NMDA channel blocker AZD6765 (Zarate et al., 2013). The NMDA receptor glycine-site functional partial agonist, GLYX-13, and its orally bioavailable and presumed more potent analog, NRX-1074, have also garnered the recent attention of researchers and clinicians (Burgdorf et al., 2013; Dolgin, 2013), as have several modulators of metabotropic glutamate receptors (e.g., the mGluR7 allosteric agonist AMN082; Bradley et al., 2012) and select α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators (e.g., Org 26576; Nations et al., 2012).
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ PR Newswire (2010). "Naurex's Novel Antidepressant GLYX-13 Recognized as One of Windhover's Top 10 Neuroscience Projects to Watch".
- ^ a b c d e PR Newswire (2014). "Naurex Reports Positive Top-Line Phase 2b Results for Novel Antidepressant GLYX-13 and Advances NRX-1074 into Phase 2 Depression Study".
- ^ Dang YH, Ma XC, Zhang JC, et al. (January 2014). "Targeting of NMDA Receptors in the Treatment of Major Depression". Curr. Pharm. Des. 20 (32): 5151–9. doi:10.2174/1381612819666140110120435. PMID 24410564.
- ^ plc, Allergan. "Allergan Successfully Completes Naurex Acquisition". www.prnewswire.com. Retrieved 2016-11-20.
- ^ "Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder". Clinicaltrials.gov. US National Institutes of Health. Retrieved 10 December 2014.
External links