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Apimostinel

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Apimostinel
Clinical data
Other namesThreonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide
Legal status
Legal status
  • Investigational New Drug
Identifiers
  • (2R)-1-[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-2-benzylpyrrolidine-2-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H37N5O6
Molar mass503.600 g·mol−1
3D model (JSmol)
  • C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N2CCC[C@@]2(Cc3ccccc3)C(=O)N[C@@H]([C@@H](C)O)C(N)=O
  • InChI=1S/C25H37N5O6/c1-15(31)19(26)23(35)29-12-6-10-18(29)22(34)30-13-7-11-25(30,14-17-8-4-3-5-9-17)24(36)28-20(16(2)32)21(27)33/h3-5,8-9,15-16,18-20,31-32H,6-7,10-14,26H2,1-2H3,(H2,27,33)(H,28,36)/t15-,16-,18+,19+,20+,25-/m1/s1
  • Key:DVBUEXCIEIAXPM-PJUQSVSOSA-N

Apimostinel (INN) (developmental code names NRX-1074, AGN-241660) 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] 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, unlike rapastinel (which must be administered via intravenous injection), is orally-active.[3] Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel. 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] 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.

Commercial competitors of the drug include PT00114 from Protagenic, Cerecor's CERC-301, and AV-101 from VistaGen Therapeutics.[8]

Commerical Aspects

Naurex

Naruex, the original company responsible for apimostinel, was a pharmaceutical company that developed drug candidates as NMDA receptor modulators, as novel, next-generation antidepressants. The company was acquired by Allergan in later 2015, who continued the clinical trials for Naurex's NMDA receptor modulator drugs. Allergan went public in 1993 as Watson Pharmaceuticals, Inc and was rebranded as Allergan in 2015 after the acquisition of several pharmaceutical companies. Allergan trades on the New York Stock Exchange under the ticker AGN. [7]

In mid 2016, the acquired Naurenx, now rebranded as Aptinyx, announced a $65 million start up round with venture capital companies including New Leaf Venture Partenrs aimed towards NMDA modulation for the treatment of Parkinson's disease and PTSD.[8]

Cost of Synthesis

Apimostinel, according to one supplier, is available in amounts > 1 gram through custom synthesis. Purity is normally >98% and has an estimated lead time of 2-3 months.[9]

Clinical Trials

Phase 2 - MDD

A phase 2 clinical trial regarding the intravenous formulation of apimostinel for the treatment of MDD was launched in early 2014. This double blind, randomized study [NCT02067793] aimed to evaluate a patients change from baseline in their Hamilton Depression Rating Scale 17 (HDRS-17) score when they take apimostinel versus a placebo group. 151 patients were admitted into the study and was completed in early 2015.[10] The study showed statistically significant improvement in depression scores within 24 hours of taking the drug dose. No drug-related adverse effects were reported and apimostinel was well tolerated across all patients. [11]

A safety study regarding the safety and pharmacokinetics of apimostinel (NRX-1074) was also done during this time [NCT01856556]. The study aimed to evaluate the safety and tolerance of a single dose of NRC-1074 as a primary objective and to determine the plasma/csf pharamacokinetics as a secondary objective. This randomized, double blind study had 100 volunteers and ran from May, 2013 to November 2014.[12]

Data regarding NRX-1074 was presented at the 2015 Society for Neuroscience Annual Meeting in Chicago from October 17-21.[13]

Phase 2- Schizophrenia

A double blind, randomized phase 2 clinical trial [NCT02603458] was planned to investigate apimostinel for the treatment of schizophrenia. However, the trials was withdrawn by Naurex prior to patient enrollment[14]

See also

References

  1. ^ 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)
  2. ^ PR Newswire (2010). "Naurex's Novel Antidepressant GLYX-13 Recognized as One of Windhover's Top 10 Neuroscience Projects to Watch".
  3. ^ 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".
  4. ^ 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.
  5. ^ plc, Allergan. "Allergan Successfully Completes Naurex Acquisition". www.prnewswire.com. Retrieved 2016-11-20.
  6. ^ "Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder". Clinicaltrials.gov. US National Institutes of Health. Retrieved 10 December 2014.
  7. ^ "Investor FAQs". Allergan. Retrieved 2016-11-20.
  8. ^ "Naurex vets reprise blockbuster NMDA R&D role with $65M startup round | FierceBiotech". www.fiercebiotech.com. Retrieved 2016-11-20.
  9. ^ "Apimostinel | NRX-1074 | AGN-241660 | CAS#1421866-48-9 | NMDA receptor | MedKoo". www.medkoo.com. Retrieved 2016-11-20.
  10. ^ "Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-20.
  11. ^ "Naurex's First Orally Active Molecule, NRX-1074, Demonstrates Statistically Significant Improvement in Depression Scores within 24 Hours in Phase 2 …". www.firstwordpharma.com. Retrieved 2016-11-20.
  12. ^ "Safety and Pharmacokinetics of NRX-1074 in Normal Volunteers - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-20.
  13. ^ plc, Allergan. "Data on Allergan's Rapastinel and NRX-1074 (AGN-241660) presented at the Society for Neuroscience (SfN) Annual Meeting". www.prnewswire.com. Retrieved 2016-11-20.
  14. ^ "NRX-1074 in Early Course Schizophrenia - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-20.

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