Chemistry:ENX-102

From HandWiki

ENX-102, also known as TPA-023B, is a GABAA receptor positive allosteric modulator, nonbenzodiazepine, and investigational anxiolytic which is under development for the treatment of generalized anxiety disorder and social phobia (social anxiety disorder).[1][2][3][4][5] It is taken orally.[1][4]

The drug is a selective and partial positive allosteric modulator of α2, α3, and α5 subunit-containing GABAA receptors, whereas it shows no activity at α1 subunit-containing GABAA receptors, and is potentially "anxioselective", producing anxiolytic effects with little or no sedation, in contrast to existing agents like benzodiazepines and Z-drugs.[1][3][4][6]

Side effects

Side effects of ENX-102 include mild and transient fatigue, tiredness, somnolence, and drowsiness.[3][4][2][7] It has also been found to produce cognitive and memory impairment.[4] The adverse effects of ENX-102 appear to be less than with lorazepam.[4] Tolerance develops to the effects and side effects of ENX-102.[4]

Pharmacology

Pharmacodynamics

ENX-102 acts as a subunit-selective positive allosteric modulator of the benzodiazepine site of the GABAA receptor.[1][3][4] More specifically, it selectively and partially potentiates GABAA receptors containing α2, α3, and α5 subunits, whilst showing no activity at as a silent allosteric modulator or functionally antagonizing GABAA receptors containing α1 subunits.[1][3][4][6]

ENX-102 activities[4]
GABAAR ENX-102 Diazepam
Emax EC50 (nM) Emax EC50 (nM)
α1β3γ2L 3% ND 140% 22.2
α2β3γ2L 89% 0.82 385% 6.19
α3β3γ2L 113% 2.47 429% 42.6
α5β3γ2L 96% 0.20 208% 15.4

The drug produces anxiolytic-like effects in animals, including in rodents and primates.[2][3][8][4][7] It produced robust anxiolytic-like effects comparable to those of chlordiazepoxide in rodents.[4][7] The drug was "anxioselective" in rodents and primates, producing no sedation at doses 10- to 30-fold higher and corresponding to receptor occupancies of greater than 98%.[3][4][7] The electroencephalogram (EEG) changes for ENX-102 were distinct from those of benzodiazepines in animals.[4] ENX-102 also showed distinct discriminative stimulus or interoceptive effects from those of lorazepam and zolpidem in rodent drug discrimination tests.[7][2][9] It generalizes with TPA-023, but not with lorazepam or zolpidem.[7][2][9]

TPA-023 showed no misuse potential in baboons, whereas ENX-102 was not assessed but may be expected to be similar.[7][2] Subsequent research has found that ENX-102 is self-administered by monkeys but shows reduced reinforcing effects compared to benzodiazepines.[10][6] In addition, ENX-102 has been found to attenuate benzodiazepine self-administration.[6] The drug also attenuated benzodiazepine withdrawal symptoms.[6] It has been suggested for the potential treatment of benzodiazepine addiction.[6]

ENX-102 has been evaluated in humans.[4][7] It reduced saccadic peak velocity (SPV), a biomarker reflecting arousal and a potential surrogate marker for anxiolysis.[4] The reduction in SPV was comparable to that with lorazepam.[4] Conversely, the drug showed minimal effects on alertness and motor coordination and did not produce sedation.[4][7] In addition, like in animals, it showed distinct EEG changes compared to benzodiazepines.[4] The GABAA receptor occupancy of ENX-102 has been studied in humans.[7][11] At approximately 50% receptor occupancy, there was no sedation with ENX-102, whereas benzodiazepines produce clear sedation at occupancies of only 15 to 24%.[7][11]

Subsequent research, based on animal studies and including ENX-102 and other agents, has suggested that α1 subunit-containing GABAA receptors may mediate moderate or deep sedation, whereas α2 and α3 subunit-containing GABAA receptors may mediate a mild form of sedation.[12]

In addition to its anxiolytic effects, ENX-102 also produces analgesic effects in animals.[13][14] In 2026, it was unexpectedly found that ENX-102's analgesic effects did not correlate with receptor occupancy at γ2 subunit-containing GABAA receptors and that the drug not only potentiated these receptors but also potentiated γ1 subunit-containing GABAA receptors that could be involved in the analgesic effects.[13]

Pharmacokinetics

ENX-102 is well-absorbed with oral administration in humans.[4] The time to peak levels is 3 to 4.5 hours.[2][4] Steady-state levels are reached after 6 days of continuous daily administration.[4] The drug accumulation ratio is 3 to 4.[4] ENX-102 levels decline biexponentially, with a terminal half-life of 25 to 66 hours.[4][2][7] There was minimal interindividual variability in the pharmacokinetics of ENX-102.[4] The pharmacokinetics of ENX-102, including oral bioavailability, have also been studied in animals.[2]

Chemistry

ENX-102 is specifically formulated as the phosphate salt.[4] The chemical synthesis of ENX-102 has been described.[15][16]

History and development

ENX-102 was first described in the scientific literature by 2005.[17][15][18][11][9] It was developed by Merck and was originally known as TPA-023B.[3] The drug was formally clinically developed by this company and appears to have reached phase 1 clinical trials.[8][2] ENX-102 is now under development by Engrail Therapeutics.[1] As of October 2025, it is in phase 2 clinical trials for treatment of social phobia and other anxiety disorders.[1] In terms of other anxiety disorders, it is specifically under development for generalized anxiety disorder.[19][5][20] The first publication on ENX-102 in the scientific literature under this specific developmental code name was published in 2022.[21][4]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "ENX 102". 28 October 2025. https://adisinsight.springer.com/drugs/800064863. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 "GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics". Current Topics in Behavioral Neurosciences 2: 331–360. 2010. doi:10.1007/7854_2009_30. PMID 21309116. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "Anxioselective anxiolytics: on a quest for the Holy Grail". Trends in Pharmacological Sciences 33 (11): 611–620. November 2012. doi:10.1016/j.tips.2012.08.003. PMID 22981367. "The third compound from the Merck development program examined in the clinic, TPA 023B, is structurally distinct from TPA 023 and MRK 409 (Fig. 1). TPA 023b binds with high affinity (0. 7–2 nM) across recombinant DS GABAA receptors and exhibited an “ideal” agonist profile: essentially null efficacy (0.03 relative to chlordiazepoxide) at α1 receptors with moderate efficacies at α 2,3, and 5 bearing receptors (0.38, 0.50, and 0.37 relative to chlordiazepoxide, respectively). Like its predecessors, TPA 023B was unequivocally anxioselective in preclinical models. Anxiolytic-like effects were reported in both primates and rodents [69] with no sedation observed at doses up to 30-fold higher, corresponding to receptor occupancies of >98% [69]. In Phase I studies, fatigue/tiredness and somnolence/drowsiness were noted in four of eight subjects at a 1 mg dose. Dose limiting adverse events at the MTD (2 mg) were fatigue and drowsiness, corresponding to a ~55% receptor occupancy determined by PET imaging [69].". 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 "Biomarker-Based Pharmacological Characterization of ENX-102, a Novel α2/3/5 Subtype-Selective GABAA Receptor Positive Allo-Steric Modulator: Translational Insights from Rodent and Human Studies". Cells 14 (20): 1575. October 2025. doi:10.3390/cells14201575. PMID 41148790. 
  5. ↑ 5.0 5.1 Engrail Therapeutics (2 September 2024). "De-risking drug development through precision neuroscience". Biopharma Dealmakers (Springer Nature Limited). https://www.nature.com/articles/d43747-024-00088-6. Retrieved 20 August 2026. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Preclinical evidence for a novel pharmacotherapeutic approach for treating benzodiazepine addiction". Translational Psychiatry 16 (1). November 2025. doi:10.1038/s41398-025-03762-0. PMID 41271639. 
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 "Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist". Journal of Psychopharmacology (Oxford, England) 25 (3): 329–344. March 2011. doi:10.1177/0269881109354928. PMID 20156926. 
  8. ↑ 8.0 8.1 "GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics". Current Topics in Medicinal Chemistry 11 (9): 1176–1202. 2011. doi:10.2174/156802611795371350. PMID 21050172. 
  9. ↑ 9.0 9.1 9.2 "Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/benzodiazepine modulator: comparisons with zolpidem, lorazepam, and TPA023". Pharmacology, Biochemistry, and Behavior 90 (1): 65–73. July 2008. doi:10.1016/j.pbb.2008.02.019. PMID 18395780. 
  10. ↑ "Reinforcing effects of compounds lacking intrinsic efficacy at α1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced rhesus monkeys". Neuropsychopharmacology 38 (6): 1006–1014. May 2013. doi:10.1038/npp.2012.265. PMID 23303046. 
  11. ↑ 11.0 11.1 11.2 "In vivo characterization and dynamic receptor occupancy imaging of TPA023B, an alpha 2/alpha 3/alpha 5 subtype selective gamma-aminobutyric acid-a partial agonist". Biological Psychiatry 64 (2): 153–161. July 2008. doi:10.1016/j.biopsych.2008.01.021. PMID 18339360. 
  12. ↑ "Evidence That Sedative Effects of Benzodiazepines Involve Unexpected GABAA Receptor Subtypes: Quantitative Observation Studies in Rhesus Monkeys". The Journal of Pharmacology and Experimental Therapeutics 366 (1): 145–157. July 2018. doi:10.1124/jpet.118.249250. PMID 29720564. 
  13. ↑ 13.0 13.1 "A PK/PD study on antihyperalgesia by an α2/3-GABAA receptor PAM in mice: Lack of tolerance liability and potential involvement of γ1-GABAA receptors". British Journal of Pharmacology 183 (10): 2324–2340. May 2026. doi:10.1111/bph.70301. PMID 41492211. 
  14. ↑ "The α2/α3GABAA receptor modulator TPA023B alleviates not only the sensory but also the tonic affective component of chronic pain in mice". Pain 162 (2): 421–431. February 2021. doi:10.1097/j.pain.0000000000002030. PMID 32773599. 
  15. ↑ 15.0 15.1 "Discovery of imidazo[1,2-b][1,2,4]triazines as GABA(A) alpha2/3 subtype selective agonists for the treatment of anxiety". Journal of Medicinal Chemistry 49 (4): 1235–1238. February 2006. doi:10.1021/jm051200u. PMID 16480260. 
  16. ↑ Bettati MG, Blurton PG, Carling WR, Chambers MS, Hallett DJ, Jennings AG, Lewis RT, Russell MG, Street LJ, Szekeres HJ, Van NM, "Imidazo-triazine derivatives as ligands for Gaba receptors", US patent 6936608, published 8 November 2001, issued 2005-08-30, assigned to Merck Sharp & Dohmeand Bettati Michela
  17. ↑ "Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-selective GABA agonist". The Journal of Organic Chemistry 70 (15): 5938–5945. July 2005. doi:10.1021/jo0507035. PMID 16018689. 
  18. ↑ "Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety". Bioorganic & Medicinal Chemistry Letters 16 (6): 1582–1585. March 2006. doi:10.1016/j.bmcl.2005.12.027. PMID 16384707. 
  19. ↑ "Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future". Neuropsychopharmacology 49 (1): 83–95. January 2024. doi:10.1038/s41386-023-01728-8. PMID 37709943. 
  20. ↑ "ENX-102, a GABA-A Alpha2, 3, 5 PAM That Blocks Alpha1, for the Treatment of Generalized Anxiety Disorder: A Phase 1 Single Ascending Dose Clinical Study.". Neuropsychopharmacology 47 (SUPPL 1): 105–106. 
  21. ↑ "Preclinical Evaluation of ENX-102, a GABAA alpha 2, 3, 5 PAM That Blocks alpha 1, in the Elevated Plus Maze and Pharmaco-EEG.". Neuropsychopharmacology 47 (SUPPL 1): 107. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:ENX-102&oldid=4645954"