ピリドキサミン
Pyridoxamine/ja
ピリドキサミン（Pyridoxamine）は、ビタミンB6の一形態である。化学的にはピリジン環構造を基本としており、ヒドロキシル、メチル、アミノメチル、ヒドロキシメチル置換基を持つ。ピリドキシンとは4位の置換基で異なる。その環の3位のヒドロキシルと4位のアミノメチル基は、ピリドキサミンに、糖や脂質の分解で形成されるフリーラジカル種やカルボニル種のスカベンジャー作用や、アマドリ反応を触媒する金属イオンのキレート化作用など、様々な化学的性質を与える。
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| Preferred IUPAC name
4-(Aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol | |
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| Properties | |
| C8H12N2O2 | |
| Molar mass | 168.196 g·mol−1 |
研究
ピリドキサミンは多くの遷移金属イオンとかなり弱い錯体を形成することができ、Cu2+とFe3+を好む。ピリドキサミンの3'-ヒドロキシル基は、効率的なヒドロキシラジカル消去を可能にする。
ピリドキサミンはメイラード反応を阻害し、糖尿病の医学的合併症に関連する高度糖化最終生成物の形成を阻害することができる。ピリドキサミンは、糖化タンパク質から放出されるアマドリ産物の形成における中間体を捕捉するという仮説がある。おそらく、酸化還元反応に重要な金属イオンとの破壊的相互作用を通じて、このプロセスの触媒作用を阻害することによって、糖化タンパク質の分解を防ぐのであろう。ある研究では、ピリドキサミンはアマドリ生成物のカルボニル基と特異的に反応するが、アマドリ後の反応（これは高度糖化最終生成物につながる）の阻害は、ピリドキサミンの金属キレート作用による部分がはるかに大きいことがわかった。
糖尿病の動物モデルを用いた様々な前臨床試験から、ピリドキサミンが 腎臓 の 組織学的 状態をアミノグアニジンと同等かそれ以上に改善することが示唆された。これらの結果から、ピリドキサミンは糖尿病性腎症の治療における臨床的有用性が検討されている。
ピリドキサミンはまた、ジカルボニル中間体との反応により、脂質過酸化反応中の高度な脂質酸化最終生成物の生成を阻害する。他の前臨床研究では、ピリドキサミンは糖尿病や腎結石疾患に伴う糖尿病性神経障害や網膜症の治療に有効である可能性がある。 ある研究では、ピリドキサミンは、現在 食品医薬品局 (FDA) に承認されている唯一の 放射線防護剤であるアミフォスチンよりも、放射性照射による 消化管 の 上皮細胞 の アポトーシス を防護するのにより効果的であった。これは、ピリドキサミンが活性酸素種 (ROS) と反応性カルボニル種 (RCS) をより効果的に捕捉する性質を持っているためです。
FDA Regulatory Activity
Pyridoxamine was marketed as a dietary supplement, often as the hydrochloride salt, pyridoxamine dihydrochloride. However, in the United States, the FDA ruled in January 2009 that pyridoxamine must be regulated as a pharmaceutical drug because it is the active ingredient in Pyridorin, a drug designed by Biostratum, Inc., to prevent the progression of diabetic nephropathy.
Pyridorin had success in early clinical trials, found to be effective in slowing the progression of diabetic neuropathy in a phase II trial on 224 patients. However, in 2005 Biostratum ran out of money and so was unable to begin a Phase III trial. Investors in Biostratum had realized that because Biostratum had no patent on pyridoxamine itself, and that pyridoxamine was commonly available for purchase as a dietary supplement, the company would be unable to charge enough money for the treatment (should it be approved as a prescription drug by the FDA) for the investors to get a reasonable return on the investment they had already made (about $100M) much less on the additional investment a Phase III trial would require. To solve this problem, Biostratum submitted a citizen petition to the FDA on July 29, 2005, seeking to disallow sales of pyridoxamine-containing supplements on the grounds that pyridoxamine, as the subject of an Investigational New Drug Application with the FDA, is a drug and not a dietary supplement. This petition was opposed by the Council for Responsible Nutrition, a trade association of the dietary supplement industry.
On January 12, 2009, the FDA ruled that products containing pyridoxamine are excluded from the definition of dietary supplements as defined by the Dietary Supplement Health and Education Act of 1994. The FDA stated that the status of Pyridorin as an investigational new drug, as a result of an application filed by BioStratum in July 1999 and effective on September 1, 1999, meant that "the marketing of pyridoxamine in a dietary supplement is essentially equivalent to the marketing of an investigational new drug as a dietary supplement" because there was an "absence of independent, verifiable evidence that the substance was marketed as a food or a dietary supplement prior to its authorization for investigation as a new drug."
In 2006, Biostratum licensed its rights in Pyridorin to another company, NephroGenex
NephroGenex conducted and completed a Phase 2b study and initiated a Phase 3 study of Pyridorin as treatment for diabetic neuropathy in patients with Type 2 diabetes. In February 24, 2016 NephroGenex was forced to pause the Phase 3 trial and ultimately terminate it later that year due to a lack of funding. The company subsequently filed for Chapter 11 bankruptcy on April 30, 2016. NephroGenex shortly thereafter sought out a corporate partner for licensing or acquisition of Pyridorin. The company retained the services of an investment banking firm which reached out to many prospective buyers, which by September 2016 had failed to consummate a transaction. NephroGenex then decided to sell all its assets, including Pyridorin, through a bankruptcy auction that was to be held on November 14, but was forced to cancel the auction after it did not receive any qualifying bids. On December 16, 2016, the company filed a motion with the bankruptcy court, proposing a liquidation plan. On August 24, 2017, the company's Investigational New Drug (IND) Applications with the FDA were withdrawn. Medpace, the Clinical Research Organization that conducted the Pyridorin Phase 3 trial, proposed and received approval for a Planned Support Agreement which transferred ownership of NephroGenex to Medpace. The new NephroGenex, renamed Medpace Research Inc., as partnered with OxiPath Health Inc. to form a new venture, ViGuard Health Inc., with the intention of marketing the oral formulation of pyridoxamine as a dietary supplement, to which end it submitted, on October 3, 2017 a citizen petition to the FDA requesting the Commissioner issue a regulation stating pyridoxamine is a dietary supplement as defined by the Dietary Supplement Health and Education Act of 1994 DSHEA).
See also
External links
- Clinical trials testing Pyridoxamine (clinicaltrials.gov):
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