EMA401

Angiotensin II is an octapeptide hormone central to the renin-angiotensin system. It regulates blood pressure control, water fluid homeostasis, and neuronal excitability.{{cite journal | vauthors = Smith MT, Wyse BD, Edwards SR | title = Small molecule angiotensin II type 2 receptor (AT₂R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats | journal = Pain Medicine | volume = 14 | issue = 5 | pages = 692–705 | date = May 2013 | pmid = 23489258 | doi = 10.1111/pme.12063 | doi-access = free }}{{cite journal | vauthors = Alterman M | title = Development of selective non-peptide angiotensin II type 2 receptor agonists | journal = Journal of the Renin-Angiotensin-Aldosterone System | volume = 11 | issue = 1 | pages = 57–66 | date = March 2010 | pmid = 19880657 | doi = 10.1177/1470320309347790 | doi-access = free }}{{ cite patent| country = US | number = 4812462 | status = patent | title = 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity| pubdate = 2006-06-29 | inventor = Blankley CJ, Hodges JC }}{{ cite patent| country = US| number = 5246943A | status = patent| title = Substituted 1,2,3,4-Tetrahydroisoquinolines with Angiotensin II Receptor Antagonist Properties | pubdate = 1993-07-21| inventor = Blanklye CJ, Hodges JC \}} 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.{{ cite patent| country = US | number = 4812462 | status = patent | title = 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity| pubdate = 2006-06-29 | inventor = Blankley CJ, Hodges JC }}{{ cite patent| country = US| number = 5385894 | status = patent| title = Disubstituted 6-aminoquinazolinones| pubdate = 1997-01-31| pridate=1997-03-06 | inventor = De Laszlo SE, Glinka TW, Greenlee WJ, Chakravarty PK, Patchett AA }} 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 (AT{{sub|1}}R) and angiotensin II type 2 receptors (AT{{sub|2}}R). AT{{sub|1}}R 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.{{cite journal | vauthors = Bauer JH, Reams GP | title = The angiotensin II type 1 receptor antagonists. A new class of antihypertensive drugs | journal = Archives of Internal Medicine | volume = 155 | issue = 13 | pages = 1361–1368 | date = July 1995 | pmid = 7794084 | doi = 10.1001/archinte.1995.00430130027004 }}

Phase I clinical trial have indicated that doses of EMA401 up to 400 mg are safe in humans.{{cite web |url=https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000977-29/CZ/ |title=CLINICAL STUDY PROTOCOL: Protocol No. EMA401-003 | work = Spinifex Pharmaceuticals Pty Limited | year = 2011}} 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.{{cite journal | vauthors = Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N, Raff M | title = 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 | journal = Lancet | volume = 383 | issue = 9929 | pages = 1637–1647 | date = May 2014 | pmid = 24507377 | doi = 10.1016/S0140-6736(13)62337-5 | s2cid = 9396522 }} 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 [https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347597 Phase 2 study of EMA401] for the treatment of pain in patients with chemotherapy-induced peripheral neuropathy was approved and is currently underway.

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 (AT{{sub|1}}R) and angiotensin II type 2 receptors (AT{{sub|2}}R).{{cite journal | vauthors = Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, Bountra C, Korchev YE, Anand P | title = Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons | journal = European Journal of Pain | volume = 17 | issue = 7 | pages = 1012–1026 | date = August 2013 | pmid = 23255326 | pmc = 3748799 | doi = 10.1002/j.1532-2149.2012.00269.x }} 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.

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.. 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.{{cite journal | vauthors = Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N, Raff M | title = 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 | journal = Lancet | volume = 383 | issue = 9929 | pages = 1637–1647 | date = May 2014 | pmid = 24507377 | doi = 10.1016/S0140-6736(13)62337-5 | s2cid = 9396522 }} 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.{{cite journal | vauthors = Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, Bountra C, Korchev YE, Anand P | title = Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons | journal = European Journal of Pain | volume = 17 | issue = 7 | pages = 1012–1026 | date = August 2013 | pmid = 23255326 | pmc = 3748799 | doi = 10.1002/j.1532-2149.2012.00269.x }}

No serious adverse effects have been observed with EMA401 in early clinical trials but there is limited evidence{{cite journal | vauthors = Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N, Raff M | title = 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 | journal = Lancet | volume = 383 | issue = 9929 | pages = 1637–1647 | date = May 2014 | pmid = 24507377 | doi = 10.1016/S0140-6736(13)62337-5 | s2cid = 9396522 }} Slightly higher frequency of complaints such as pharyngitis, headaches and allergic dermatitis are reported by individuals taking EMA401. Headache frequency was higher in patients receiving EMA401 over placebo in both phase 1 and phase 2 clinical trials for EMA401.

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Category:Drugs acting on the nervous system

Category:Receptor antagonists