Chemistry:XC-101

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XC-101, or XC101, also known as XC101-D13H, is a non-selective serotonin receptor modulator which is under development for the prevention of migraine.[1][2][3][4][5] It is taken orally.[1][4][2]

The drug acts as an agonist of the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT7 receptors and as an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, with varying potencies at these targets.[1][4] Its antimigraine preventative efficacy is thought to derive specifically from its serotonin 5-HT2B and 5-HT2C receptor antagonism, although its serotonin 5-HT1D and 5-HT1B receptor agonism may also contribute.[4][6][7][8] Due to its lack of agonism at the serotonin 5-HT2A and 5-HT2B receptors and at the α1A-adrenergic receptor, XC-101 is thought to avoid adverse effects and toxicity including hallucinogenic effects, cardiac fibrosis and valvulopathy, and vasoconstriction.[4] The pharmacokinetics and tolerability of XC-101 at doses of 0.2 to 0.5 mg orally in humans have been studied.[6][7][4]

Besides XC-101, its developer has also studied ergoline antimigraine agents like methysergide.[9][10][3][5][2] XC-101 has been compared to methysergide, which was described as being effective for migraine prevention but as having serious side effects due to undesirable off-target activities.[3][5] Whereas methysergide is functionally an agonist of the serotonin 5-HT2B receptor due to its active metabolite methylergometrine, XC-101 is a silent antagonist of the receptor.[9][4] In addition, whereas methysergide was found to be a full agonist of the serotonin 5-HT2A receptor, which is associated with psychedelic effects, XC-101 was likewise a silent antagonist of the receptor.[9][4]

File:D13H structure.svg
D13H structure.[11]

XC-101 was first described in the scientific literature by 2019.[3][5][4] It is under development by Xoc Pharmaceuticals.[1] As of November 2022, the drug is in phase 1/2 clinical trials for migraine prevention.[1] The chemical structure of XC-101 does not yet appear to have been disclosed.[1] However, Xoc Pharmaceuticals patented an ergoline antimigraine compound with code name "D13H" in 2019 and this compound may be XC101-D13H (XC-101).[11] It is the 2-cyclopropyl and 9,10-dihydro analogue of methysergide (or 2-cyclopropyl-9,10-dihydromethysergide).[11]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "XC 101". 28 November 2022. https://adisinsight.springer.com/drugs/800051258. 
  2. ↑ 2.0 2.1 2.2 "The Headache Pipeline: Excitement and Uncertainty". Headache 60 (1): 190–199. January 2020. doi:10.1111/head.13728. PMID 31889312. 
  3. ↑ 3.0 3.1 3.2 3.3 "P182 Development of a Novel, Clinical-stage Drug for the Prevention of Migraine Based on Receptor Activity Mapping and Achievement of a Target Receptor Profile". Headache: The Journal of Head and Face Pain. 61st Annual Scientific Meeting American Headache Society ® July 11 -14 2019 (Pennsylvania Convention Center Philadelphia, PA) 59 (S1): 1–208. 2019. doi:10.1111/head.13549. ISSN 0017-8748. PMID 31290138. https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_2_XocPharma_Final.pdf. Retrieved 2026-01-25. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "Interim Results of a Phase 1 Single Ascending Dose Study of XC101-D13H, a Novel Compound for the Prevention of Migraine". Headache: The Journal of Head and Face Pain. 62nd Annual Scientific Meeting American Headache Society 60 (S1): 1–156. 2020. doi:10.1111/head.13854. ISSN 0017-8748. PMID 32533851. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.13854. Retrieved 24 January 2026. 
  5. ↑ 5.0 5.1 5.2 5.3 "Development of a Novel, Clinical-stage Drug for the Prevention of Migraine Based on Receptor Activity Mapping and Achievement of a Target Receptor Profile (4409)". Neurology 96 (15_supplement). 13 April 2021. doi:10.1212/WNL.96.15_supplement.4409. ISSN 0028-3878. https://www.neurology.org/doi/10.1212/WNL.96.15_supplement.4409. Retrieved 24 January 2026. 
  6. ↑ 6.0 6.1 "Recently approved and emerging drug options for migraine prophylaxis". Expert Opinion on Pharmacotherapy 23 (11): 1325–1335. August 2022. doi:10.1080/14656566.2022.2102420. PMID 35850597. "Regarding their use in prophylaxis, a recent phase I trial of a 5-HT2B/2C receptor antagonist, XC101-D13H (NCT04104399), has shown promising tolerability during its daily use [100]. This could lead to a possible prophylactic therapy with a daily use. Further studies are needed to evaluate its effectiveness.". 
  7. ↑ 7.0 7.1 "Future prophylactic treatments in migraine: Beyond anti-CGRP monoclonal antibodies and gepants". Revue Neurologique 177 (7): 827–833. September 2021. doi:10.1016/j.neurol.2021.06.005. PMID 34294458. "In July 2020, preliminary results of a phase I trial of XC101-D13H (NCT04104399), a 5-HT2B/2C receptor antagonist, demonstrated promising tolerability in healthy volunteers and suitable pharmacokinetics for daily oral dosing [16]. Nevertheless, confirmatory phase II-III trials are needed to determine efficacy, tolerability, and safety.". 
  8. ↑ "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia 37 (4): 365–371. April 2017. doi:10.1177/0333102416646760. PMID 27127104. https://nbn-resolving.org/urn:nbn:de:bvb:29-opus4-112198. 
  9. ↑ 9.0 9.1 9.2 "P179 and DB7 Novel Receptor Activity Mapping of Methysergide and Its Metabolite, Methylergometrine, Provides a Mechanistic Rationale for Both the Clinically Observed Efficacy and Risk of Fibrosis in Patients with Migraine". Headache: The Journal of Head and Face Pain. 61st Annual Scientific Meeting American Headache Society July 11-14 2019 (Pennsylvania Convention Center Philadelphia, PA) 59 (S1): 1–208. 2019. doi:10.1111/head.13549. ISSN 0017-8748. PMID 31290138. https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_1_XocPharma_Final.pdf. Retrieved 2026-01-25. 
  10. ↑ "P180 Serotonin Receptor Activity Profiles (5-HT2B and 5-HT2A) for Nine Commercialized Ergot Alkaloids Correspond to Known Risks of Fibrosis and Hallucinations". Headache: The Journal of Head and Face Pain. 61st Annual Scientific Meeting American Headache Society July 11-14 2019 (Pennsylvania Convention Center Philadelphia, PA) 59 (S1): 1–208. 2019. doi:10.1111/head.13549. ISSN 0017-8748. https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_3_XocPharma_Final.pdf. Retrieved 2026-01-25. 
  11. ↑ 11.0 11.1 11.2 Armer T, Borland S, Guzman M, "Polycyclic compounds and uses thereof", US patent 10815235B2, issued 27 October 2020



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