Pyridoxamine

Pyridoxamine
Names
IUPAC name
4-(aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol
Identifiers
85-87-0 YesY
ChEBI CHEBI:16410 YesY
ChEMBL ChEMBL593019 YesY
ChemSpider 1023 YesY
Jmol interactive 3D Image
KEGG C00534 YesY
PubChem 1052
UNII 6466NM3W93 YesY
Properties
C8H12N2O2
Molar mass 168.20 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Pyridoxamine is one form of vitamin B6. Chemically it is based on a pyridine ring structure, with hydroxyl, methyl, aminomethyl, and hydroxymethyl substituents. It differs from pyridoxine by the substituent at the 4-position. The phenol at position 3 and aminomethyl group at position 4 of its ring endow pyridoxamine with a variety of chemical properties, including the scavenging of free radical species and carbonyl species formed in sugar and lipid degradation and chelation of metal ions that catalyze Amadori reactions.[1]

Research

Pyridoxamine can form fairly weak complexes with a number of transition metal ions, with a preference for Cu2+ and Fe3+.[2] The 3'-hydroxyl group of pyridoxamine allows for efficient hydroxyl radical scavenging.[2]

Pyridoxamine inhibits the Maillard reaction and can block the formation of advanced glycation endproducts,[3] which are associated with medical complications of diabetes.[4] Pyridoxamine is hypothesized to trap intermediates in the formation of Amadori products released from glycated proteins, possibly preventing the breakdown of glycated proteins by disrupting the catalysis of this process through disruptive interactions with the metal ions crucial to the redox reaction.[5] One research study found that pyridoxamine specifically reacts with the carbonyl group in Amadori products, but inhibition of post-Amadori reactions (that can lead to advanced glycation endproducts) is due in much greater part to the metal chelation effects of pyridoxamine.[1]

A variety of preclinical studies in animal models of diabetes indicated that pyridoxamine improved kidney histology comparable or superior to aminoguanidine.[5] Because of these results, pyridoxamine has been investigated for clinical utility in the treatment of diabetic nephropathy.[5][6]

Pyridoxamine also inhibits the formation of advanced lipoxidation endproducts during lipid peroxidation reactions by reaction with dicarbonyl intermediates.[7] In other preclinical research, pyridoxamine may be efficacious in treating diabetic neuropathy and retinopathy associated with diabetes[5][7] and kidney stone disease.[2] In one study, pyridoxamine was more effective at protecting from ionizing radiation-induced gastrointestinal epithelial apoptosis than amifostine (the only radioprotector currently Food and Drug Administration (FDA)-approved) due to pyridoxamine reactive oxygen species and reactive carbonyl species scavenging profile.[8]

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.[9][10][11][12]

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.[10] However, in 2005 Biostratum ran out of money and so was unable to begin a Phase III trial.[10] 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.[10] 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.[10] This petition was opposed by the Council for Responsible Nutrition, a trade association of the dietary supplement industry.[10]

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.[11] 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."[13]

In 2006, Biostratum licensed its rights in Pyridorin to another company, NephroGenex [14] In 2008, NephroGenex restarted the clinical development of Pyridorin, which as of 2012 is still ongoing.[15]

Patenting Activity

A patent application claiming pharmaceutical compositions of pyridoxamine, and methods to use pyridoxamine to treat diabetic complications, was filed by Biostratum and was published in 2004.[16] The application does not claim pyridoxamine itself.

See also

References

  1. 1 2 Adrover M, Vilanova B, Frau J, Muñoz F, Donoso J (May 2008). "The pyridoxamine action on Amadori compounds: A reexamination of its scavenging capacity and chelating effect". Bioorg. Med. Chem. 16 (10): 5557–69. doi:10.1016/j.bmc.2008.04.002. PMID 18434162.
  2. 1 2 3 Voziyan PA, Hudson BG (2005). "Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage". Cell. Mol. Life Sci. 62 (15): 1671–81. doi:10.1007/s00018-005-5082-7. PMID 15905958.
  3. ↑ Voziyan PA, Hudson BG (2005). "Pyridoxamine: the many virtues of a maillard reaction inhibitor". Ann. N. Y. Acad. Sci. 1043 (1): 807–16. doi:10.1196/annals.1333.093. PMID 16037308.
  4. ↑ Ahmed N, Thornalley PJ (2007). "Advanced glycation endproducts: what is their relevance to diabetic complications?". Diabetes Obes Metab 9 (3): 233–45. doi:10.1111/j.1463-1326.2006.00595.x. PMID 17391149.
  5. 1 2 3 4 Giannoukakis N (2005). "Pyridoxamine (BioStratum)" (PDF). Curr Opin Investig Drugs 6 (4): 410–8. PMID 15898348.
  6. ↑ Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill JB (2007). "Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy". Am. J. Nephrol. 27 (6): 605–14. doi:10.1159/000108104. PMID 17823506.
  7. 1 2 Metz TO, Alderson NL, Thorpe SR, Baynes JW (2003). "Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications". Arch. Biochem. Biophys. 419 (1): 41–9. doi:10.1016/j.abb.2003.08.021. PMID 14568007.
  8. ↑ Thotala D, Chetyrkin S, Hudson B, Hallahan D, Voziyan P, Yazlovitskaya E (September 2009). "Pyridoxamine protects intestinal epithelium from ionizing radiation-induced apoptosis". Free Radic. Biol. Med. 47 (6): 779–85. doi:10.1016/j.freeradbiomed.2009.06.020. PMC 2739572. PMID 19540915.
  9. ↑ "FDA finds vitamin B6 form not legal in supplements", newsfood.com, February 2, 2009
  10. 1 2 3 4 5 6 "Big problem for BioStratum", Triangle Business Journal, October 14, 2005
  11. 1 2 "FDA's pyridoxamine decision: FDA's decision regarding pyridoxamine has larger implications for dietary ingredients in general", Entrepreneur, April, 2009
  12. ↑ http://www.regulations.gov/#!documentDetail;D=FDA-2005-P-0259-0004
  13. ↑ FDA-2005-P-0259-0004: FDA Response to Biostratum, Inc. (Kathleen M Sanzo, Esq) - Petition Partial Approved and Denial
  14. ↑ http://www.renalbusiness.com/news/2006/05/nephrogenex-acquires-rights-to-diabetic-nephropat.aspx
  15. ↑ http://www.nephrogenex.com/NGX_News.htm
  16. ↑ (WO/2004/112788) PYRIDOXAMINE FOR THE TREATMENT OF DIABETIC KIDNEY DISEASE, World Intellectual Property Organization

External links

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