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EMA401 is a new drug under development for the treatment of peripheral neuropathic pain. It was recently established as a potential drug option for patients suffering pain caused by postherpetic neuralgia. It may also be useful for treating various types of chronic neuropathic pains caused by lesions and other diseases affecting the somatosensory system in addition to postherpetic neuralgia. EMA401 has been implicated in alleviating pains associated with a host of neural abnormalities, ranging from excessive nerve sprouting due to damaged nerve caused by shingles, diabetes, osteoarthritis, HIV and chemotherapy. EMA401 is a competitive antagonist of angiotensin II type 2 receptor (ATR) being developed by the Australian biotechnology company (Spinifex Pharmaceuticals ). It is the S-enantiomer form of the racemate drug EMA400. Analgesic treatments currently available for pain disorders are unsuited for severe chronic neuropathic pains. EMA401 is more effective and has virtually no central nervous system side effects in comparison to current drugs for pain relief, such as Neurotin and Lyrica. Pain pathways of the other functional systems have major molecular and mechanistic differences compared to pain pathways of the peripheral nervous system. EMA401 target proteins, angiotensin II type 2 receptors, are extremely important for nociception within the peripheral nervous system and less so for nociception within other functional systems. EMA401 is the first drug on the market that targets angiotensin II type 2 receptors (ATR) with high affinity but has a low affinity for angiotensin II type 1 receptors. Angiotensin II receptor antagonists that have existed in the pharmaceutical market have had higher affinities for angiotensin II type 1 receptors (ATR) over type 2 receptors. ATR are not involved with nociception. ATR antagonists have been mostly used for the treatment of hypertension. == 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. 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. 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 (ATR) and angiotensin II type 2 receptors (ATR). ATR 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. Drugs that antagonize ATR have become used as common treatments for hypertension and congestive heart failure. Functions of ATR were unknown in comparison. Development of selective ATR agonists and antagonists aided the discovery of ATRs' functional roles within the nervous system. 4,5,6,7-tetrahydro-1H-imidazo()pyridine derivatives were the first compounds described to have antagonizing properties at the AT2 receptors. Inventors at Warner-Lambert Company LLC substituted 1,2,3,4-tetrahydroisoquinoline with various functional groups to create numerous compounds of formula I that had improved affinity for ATR. EMA400, the racemate drug to EMA401, was originally Compound 6, one of the 48 compounds of formula I. Compound 6 had higher binding affinity for ATR, compared to the other 48 compounds, with an IC value of 2.8 nM in a rabbit uterus binding assay. It was also inactive in the ATR binding assay at concentrations of 10-5 M, suggesting high selectivity for ATR. Example 47, the S-enantiomer of Compound 6 and later named EMA401, was at the time an unanalyzed compound of formula I. Compound 6, under the name PD-126,055, and five other ATR antagonists (PD-123,319, L-159,686, PD-121,981, L-161,638 and L-163,579) were reported to have previously unknown analgesic properties by investigators from the University of Queensland. Greater understanding of the pathobiology of neuropathic pain had been and still is of high demand, as is better neuropathic pain relief medication. By 2020, the neuropathic pain treatment market is projected to reach $3.6 billion USD. The report on those six drugs was the first to clearly elucidate the role of angiotensin II type 2 receptors in neuropathic pain and implicated ATR antagonists as potential drugs for the treatment of neuropathic pain. Angiotensin II AT2 receptors are produced locally in nociceptive tissues. Nociceptive neurons express only ATR, not ATR. PD-123,319, commonly used in early angiotensin II research for its moderate inhibition of ATR, blocks angiotensin II induced neuronal excitability in cultured cells of neuronal origins and also in cultured dorsal root ganglion neurons from adult rats. The family of small molecule inhibitors of angiotensin II activity on ATR, EMA200 (PD-123,319), EMA300 (PD-121,981), and EMA400 (PD-126,055), relieved hindpaw sensitivity in (a rat model of neuropathic pain ) in a recent study conducted at University of Queensland. Relief of hindpaw hypersensitivity was dose dependent. EMA400 had the highest antineuropathic potency, 60-fold more potent than EMA300 and 250-fold more potent than EMA200. EMA400 had an IC of 75.2 nM for rat ATR and an IC of 2.9x10 nM for rat ATR. EMA400, a racemate, was separated into EMA401, the S-enantiomer of EMA400, and EMA402, the R-enantiomer of EMA400. EMA401 had an IC of 39 nM for human ATR, compared to EMA402 with an IC of 1,100 nM for human ATR. EMA401 was selected as the candidate drug for neuropathic pain treatment for clinical development. Animal studies, five Phase I clinical trials, unpublished data at Spinifex Pharmaceuticals, implicated a dose range of 10–50 mg per day of EMA401 to be effective on human beings. Phase I clinical trial also indicated EMA401 dose of up to 400 mg to be safe. Spinifex Pharmaceuticals reported the results of a phase 2 clinical trial results in which 183 patients with postherpetic neuralgia received either oral EMA401 or placebo for 28 days. Those assigned to the active condition receiving EMA401 reported significantly less postherpetic neuralgia, a chronic neuropathic pain, compared to those in the placebo condition. 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. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「EMA401」の詳細全文を読む スポンサード リンク
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