EMA401
Clinical data
Routes of
administration		Oral
Legal status
Legal status
  • Phase II Clinical Trials
Pharmacokinetic data
Bioavailability33%
Protein bindingAngiotensin II Subtype 2 Receptor
Elimination half-life6-12 hr
Identifiers
  • (S)-2-(Diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC32H29NO5
Molar mass507.586 g·mol−1
3D model (JSmol)
Specific rotation+
Density1.256±0.06 g/cm3
Boiling point745.3 ± 60.0 °C (1,373.5 ± 108.0 °F)
Solubility in water14 mg/mL (20 °C)
  • COC1=C(C2=C(CN(C(C2)C(=O)O)C(=O)C(C3=CC=CC=C3)C4=CC=CC=C4)C=C1)OCC5=CC=CC=C5
  • InChI=1S/C32H29NO5/c1-37-28-18-17-25-20-33(31(34)29(23-13-7-3-8-14-23)24-15-9-4-10-16-24)27(32(35)36)19-26(25)30(28)38-21-22-11-5-2-6-12-22/h2-18,27,29H,19-21H2,1H3,(H,35,36)
  • Key:GHBCIXGRCZIPNQ-UHFFFAOYSA-N

EMA401 is a drug under development for the treatment of peripheral neuropathic pain. Trials were discontinued in 2015, with new trials scheduled to begin March, 2018.[1] It was initially established as a potential drug option for patients suffering pain caused by postherpetic neuralgia.[2] It may also be useful for treating various types of chronic neuropathic pain [3] EMA401 has shown efficacy in preclinical models of shingles, diabetes, osteoarthritis, HIV and chemotherapy.[4][5][6][7] EMA401 is a competitive antagonist of angiotensin II type 2 receptor (AT2R) being developed by the Australian biotechnology company Spinifex Pharmaceuticals. EMA401 target angiotensin II type 2 receptors, which may have importance for painful sensitisation.[8]

History of drug development

Angiotensin II is an octapeptide hormone central to the renin-angiotensin system. It regulates blood pressure control, water fluid homeostasis, and neuronal excitability.[9][10][11][12] Receptor agonists and antagonist of angiotensin II receptors that target various parts of the complicated renin-angiotensin system were developed to increase knowledge of the renin-angiotensin system and aid the development of antihypertensive drug candidates.[13][14] These investigations led to the discovery of two subtypes of membrane bound G protein-coupled angiotensin receptors within the renin-angiotensin system with vastly different functions: angiotensin II type 1 receptors (AT1R) and angiotensin II type 2 receptors (AT2R). AT1R is the receptor subtype that was found to be mainly responsible for blood pressure, water fluid regulation, and other classical known physiological actions of angiotensin II on the renin-angiotensin system.[15]

Phase I clinical trial have indicated that doses of EMA401 up to 400 mg are safe in humans.[16] Spinifex Pharmaceuticals reported the results of a phase 2 randomised placebo controlled - clinical trial results in which 183 patients with postherpetic neuralgia received either oral EMA401 or placebo for 28 days.[17] Those assigned to EMA401 reported significantly less pain associated with post-herpetic neuralgia although the improvement was modest (6.9% better than placebo on a ten point pain scale). There was no evidence of any serious side effects caused by EMA401. Spinifex Pharmaceuticals plans to proceed with larger phase II clinical trial to test higher doses for longer periods of time. A nonrandomized Phase 2 study of EMA401 for the treatment of pain in patients with chemotherapy-induced peripheral neuropathy was approved and is currently underway.

Mechanism of action

Angiotensin II (AngII) is an octapeptide that regulates blood pressure, controls water fluid balance, and pain perception. It activates two G protein-coupled receptors: angiotensin II type 1 receptors (AT1R) and angiotensin II type 2 receptors (AT2R).[18] AngII co-localized in neurons that express substance P and calcitonin gene-related peptide suggesting its presence in nociceptors (noxious-stimuli sensing neurons). EMA401 may alleviate pain and provides relief by blocking the AngII induced potentiation which is thought to be coupled to protein kinase A.

Pharmacokinetics

EMA401 is the sodium-salt form of (S)-2-(diphenylacetyl)-l,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)- 3-isoquinoline carboxylic acid. EMA401 dose of up to 400 mg was tested in healthy male adults without any major adverse effects..[16] EMA401 has been administered orally at a standardized dose of 100 mg twice daily. EMA401 reaches a maximum plasma concentration of 1000 ug/L one-hour after administration of 100 mg of EMA401 in both men and women, as observed in a phase II trial.[19] EMA401 has an elimination half-life of 6 hours on day 1 of drug intake increasing to 12 hours by day seven of drug intake. Total plasma concentration of EMA401 is consistent over 28 days. A steady state of minimum drug plasma concentration is reached by the 8th day of being on the drug. EMA401 does not accumulate in the blood at presently administered doses. EMA401 does not cross the blood-brain barrier, therefore has little effect on the central nervous system.[20]

Adverse effects

No serious adverse effects have been observed with EMA401 in early clinical trials but there is limited evidence[21] Slightly higher frequency of complaints such as pharyngitis, headaches and allergic dermatitis are reported by individuals taking EMA401.[16] Headache frequency was higher in patients receiving EMA401 over placebo in both phase 1 and phase 2 clinical trials for EMA401.

References

  1. ↑ "EMA401 clinical trials". clinicaltrials.gov. Retrieved 2017-02-10.
  2. ↑ Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, et al. (May 2014). "EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial". Lancet. 383 (9929): 1637–1647. doi:10.1016/S0140-6736(13)62337-5. PMID 24507377. S2CID 9396522.
  3. ↑ Sumners C, Horiuchi M, Widdop RE, McCarthy C, Unger T, Steckelings UM (August 2013). "Protective arms of the renin-angiotensin-system in neurological disease". Clinical and Experimental Pharmacology & Physiology. 40 (8): 580–588. doi:10.1111/1440-1681.12137. PMID 23735163.
  4. ↑ WO patent 2006066361, Smith MT, Wyse BD, "Methods of Treatment or Prophylaxis", published 2006-06-29
  5. ↑ WO patent 2011088504, MCCARTHY THOMAS DAVID; BAKER ANDREW RAINSFORD, "METHODS AND COMPOSITIONS FOR IMPROVED NERVE CONDUCTION VELOCITY", published 2006-06-29
  6. ↑ Sumners C, Horiuchi M, Widdop RE, McCarthy C, Unger T, Steckelings UM (August 2013). "Protective arms of the renin-angiotensin-system in neurological disease". Clinical and Experimental Pharmacology & Physiology. 40 (8): 580–588. doi:10.1111/1440-1681.12137. PMID 23735163.
  7. ↑ Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, et al. (August 2013). "Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons". European Journal of Pain. 17 (7): 1012–1026. doi:10.1002/j.1532-2149.2012.00269.x. PMC 3748799. PMID 23255326.
  8. ↑ WO patent 2006066361, Smith MT, Wyse BD, "Methods of Treatment or Prophylaxis", published 2006-06-29
  9. ↑ Smith MT, Wyse BD, Edwards SR (May 2013). "Small molecule angiotensin II type 2 receptor (AT₂R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats". Pain Medicine. 14 (5): 692–705. doi:10.1111/pme.12063. PMID 23489258.
  10. ↑ Alterman M (March 2010). "Development of selective non-peptide angiotensin II type 2 receptor agonists". Journal of the Renin-Angiotensin-Aldosterone System. 11 (1): 57–66. doi:10.1177/1470320309347790. PMID 19880657.
  11. ↑ US patent 4812462, Blankley CJ, Hodges JC, "4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity", published 2006-06-29
  12. ↑ US patent 5246943A, Blanklye CJ, Hodges JC \, "Substituted 1,2,3,4-Tetrahydroisoquinolines with Angiotensin II Receptor Antagonist Properties", published 1993-07-21
  13. ↑ US patent 4812462, Blankley CJ, Hodges JC, "4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity", published 2006-06-29
  14. ↑ US patent 5385894, De Laszlo SE, Glinka TW, Greenlee WJ, Chakravarty PK, Patchett AA, "Disubstituted 6-aminoquinazolinones", published 1997-01-31
  15. ↑ Bauer JH, Reams GP (July 1995). "The angiotensin II type 1 receptor antagonists. A new class of antihypertensive drugs". Archives of Internal Medicine. 155 (13): 1361–1368. doi:10.1001/archinte.1995.00430130027004. PMID 7794084.
  16. 1 2 3 "CLINICAL STUDY PROTOCOL: Protocol No. EMA401-003". Spinifex Pharmaceuticals Pty Limited. 2011.
  17. ↑ Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, et al. (May 2014). "EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial". Lancet. 383 (9929): 1637–1647. doi:10.1016/S0140-6736(13)62337-5. PMID 24507377. S2CID 9396522.
  18. ↑ Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, et al. (August 2013). "Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons". European Journal of Pain. 17 (7): 1012–1026. doi:10.1002/j.1532-2149.2012.00269.x. PMC 3748799. PMID 23255326.
  19. ↑ Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, et al. (May 2014). "EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial". Lancet. 383 (9929): 1637–1647. doi:10.1016/S0140-6736(13)62337-5. PMID 24507377. S2CID 9396522.
  20. ↑ Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, et al. (August 2013). "Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons". European Journal of Pain. 17 (7): 1012–1026. doi:10.1002/j.1532-2149.2012.00269.x. PMC 3748799. PMID 23255326.
  21. ↑ Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, et al. (May 2014). "EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial". Lancet. 383 (9929): 1637–1647. doi:10.1016/S0140-6736(13)62337-5. PMID 24507377. S2CID 9396522.
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