XC-101

Last updated

XC-101
Clinical data
Other namesXC101; XC101-D13H; XC-101-D13H
Routes of
administration 		Oral [1] [2] [3]
Drug class Serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT7 receptor agonist; Serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor antagonist; Antimigraine agent
Pharmacokinetic data
Onset of action 2–3 hours (Tmax Tooltip time to peak levels) [2]
Elimination half-life 10–15 hours [2]

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] [3] [4] [2] [5] It is taken orally. [1] [2] [3]

Contents

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] [2] 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. [2] [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. [2] The pharmacokinetics and tolerability of XC-101 at doses of 0.2 to 0.5 mg orally in humans have been studied. [6] [7] [2]

Besides XC-101, its developer has also studied ergoline antimigraine agents like methysergide. [9] [10] [4] [5] [3] 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. [4] [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] [2] 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] [2]

D13H structure. D13H structure.svg
D13H structure.

XC-101 was first described in the scientific literature by 2019. [4] [5] [2] 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 2 3 4 5 6 7 "XC 101". AdisInsight. 28 November 2022. Retrieved 24 January 2026.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Fishman RS, Forst AR, Guzman M, Armer TA, Borland SW, Rapoport AM (2020). "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. doi:10.1111/head.13854. ISSN   0017-8748. PMID   32533851 . Retrieved 24 January 2026.
  3. 1 2 3 4 Rapoport AM, McAllister P (January 2020). "The Headache Pipeline: Excitement and Uncertainty". Headache. 60 (1): 190–199. doi:10.1111/head.13728. PMID   31889312.
  4. 1 2 3 4 Armer TA, Guzman M, Borland SW, Fishman RS, Leyden MJ (2019). "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" (PDF). Headache: The Journal of Head and Face Pain. 61st Annual Scientific Meeting American Headache Society ® July 11 -14 2019. 59 (S1). Pennsylvania Convention Center Philadelphia, PA: 1–208. doi:10.1111/head.13549. ISSN   0017-8748. PMID   31290138. Archived from the original on 2019-09-16. Retrieved 2026-01-25.{{cite journal}}: CS1 maint: bot: original URL status unknown (link)
  5. 1 2 3 4 Guzman M, Borland S, Fishman R, Armer T (13 April 2021). "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) 4409. doi:10.1212/WNL.96.15_supplement.4409. ISSN   0028-3878 . Retrieved 24 January 2026.
  6. 1 2 Bentivegna E, Luciani M, Ferrari V, Galastri S, Baldari F, Scarso F, et al. (August 2022). "Recently approved and emerging drug options for migraine prophylaxis". Expert Opinion on Pharmacotherapy. 23 (11): 1325–1335. 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. 1 2 Do TP, Al-Saoudi A, Ashina M (September 2021). "Future prophylactic treatments in migraine: Beyond anti-CGRP monoclonal antibodies and gepants". Revue Neurologique. 177 (7): 827–833. 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. ↑ Segelcke D, Messlinger K (April 2017). "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia. 37 (4): 365–371. doi:10.1177/0333102416646760. PMID   27127104.
  9. 1 2 3 Guzman M, Armer TA, Borland SW, Fishman RS, Leyden MJ (2019). "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" (PDF). Headache: The Journal of Head and Face Pain. 61st Annual Scientific Meeting American Headache Society July 11-14 2019. 59 (S1). Pennsylvania Convention Center Philadelphia, PA: 1–208. doi:10.1111/head.13549. ISSN   0017-8748. PMID   31290138. Archived from the original (PDF) on 2019-09-16. Retrieved 2026-01-25.
  10. ↑ Armer T, Guzman M, Borland S, Fishman R, Leyden M, Rapoport AM (2019). "P180 Serotonin Receptor Activity Profiles (5-HT2B and 5-HT2A) for Nine Commercialized Ergot Alkaloids Correspond to Known Risks of Fibrosis and Hallucinations" (PDF). Headache: The Journal of Head and Face Pain. 61st Annual Scientific Meeting American Headache Society July 11-14 2019. 59 (S1). Pennsylvania Convention Center Philadelphia, PA: 1–208. doi:10.1111/head.13549. ISSN   0017-8748. Archived from the original on 2022-03-04. Retrieved 2026-01-25.{{cite journal}}: CS1 maint: bot: original URL status unknown (link)
  11. 1 2 3 US 10815235B2,Armer T, Borland S, Guzman M,"Polycyclic compounds and uses thereof",issued 27 October 2020, assigned to Xoc Pharmaceuticals, Inc.
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