Pimagedine

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Pimagedine
Skeletal formula of a pimagedine Aminoguanidin.svg
Skeletal formula of a pimagedine
Spacefill model of a pimagedine Aminoguanidine sf.png
Spacefill model of a pimagedine
Names
IUPAC name
2-Aminoguanidine
Other names
  • Aminoguanidine
  • Guanyl hydrazine
  • Hydrazinecarboximidamide
  • Imino semicarbazide
  • Monoaminoguanidine
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.001.076 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/CH6N4/c2-1(3)5-4/h1,4H,2-3H2 X mark.svgN
    Key: DRCHNMARIZRTKI-UHFFFAOYSA-N X mark.svgN
  • NC(N)N=N
Properties
CH6N4
Molar mass 74.085 g/mol
Density 1.72 g/ml
Boiling point 261 °C (502 °F; 534 K)
log P −1.475
Related compounds
Related compounds
 Guanidine
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Pimagedine, also known as aminoguanidine, is an investigational drug for the treatment of diabetic nephropathy that is no longer under development as a drug. [1] Pimagedine functions as an inhibitor of diamine oxidase and nitric oxide synthase. It acts to reduce levels of advanced glycation end products (AGEs) through interacting with 3-deoxyglucosone, glyoxal, methylglyoxal, and related dicarbonyls. These reactive species are converted to less reactive heterocycles by this condensation reaction.

Contents

History

Pimagedine was under development as a drug for kidney diseases by the pharmaceutical company Alteon (now known Synvista Therapeutics Inc.) that was founded in 1986. [2] In 1987, Alteon acquired a license to intellectual property relating to AGE inhibition from Rockefeller University. [3] In 1989, Alteon and Marion Merrell Dow Inc (MMD) entered into a joint development program for pimagedine. [4] In 1992, Alteon licensed a patent from Rockefeller University relating to the use of pimagedine to inhibit AGE formation. [3] In 1995, Hoechst AG (now Sanofi-Aventis) acquired MMD and subsequently terminated its agreement with Alteon, which led Alteon to stop clinical trials, which caused some controversy. [4] In 1997, Alteon and Genentech announced a collaboration under which Genentech would fund development of pimagedine and would have the rights to sell the drug if it would be approved. [5]

In March 1998, Alteon announced that it had been advised that it should discontinue its Phase III trial of pimagedine in non-insulin-dependent (type II) diabetes patients with overt nephropathy, after the trial's external safety monitoring committee found an increased risk of side effects in the treatment group. [6] In November 1998, Alteon announced that its Phase III trial for pimagedine as a treatment for end stage renal disease had failed to prove efficacy, which led Carl Gordon, a leading biotech analyst, to say: "It looks like pimagedine is probably finished." [7] In February, 1999, Genentech ended its collaboration with Alteon to develop pimagedine. [8] In April 1999 Alteon announced that it would cease development of pimagedine as a treatment for end stage renal disease but might consider continuing development in type 1 diabetic patients with overt nephropathy or progressive kidney disease. [9] Alteon's 2000, 2001, 2002 annual reports indicated that it was not running any clinical trials on pimagedine but was seeking co-development partners. [10] [11] [12] Alteon's 2003 and subsequent annual reports did not mention that Alteon was seeking partners for pimagedine, [13] which indicated that efforts to interest other companies and investors had failed and which signaled that commercial efforts to develop pimagedine as a drug were indeed finished.[ citation needed ]

Chemistry

Synthesis

The industrial synthesis uses the reaction between cyanamide and hydrazine in aqueous solution. [14]

Aminoguanidine synthesis01.svg

The compound can also be obtained from the reduction of nitroguanidine with zinc in acetic acid. [15]

Properties

Aminoguanidine is a colorless solid that is soluble in water and ethanol. It is basic, producing salts when reacted with organic acids. As established by many crystallographic studies, protonation of aminoguanidine occurs at the imino nitrogen. [16] With formic acid, condensation occurs, leading to cyclization to give 3-amino-1,2,4-triazole. [14]

3-Amino-1,2,4-triazole synthesis01.svg

The compound reacts with nitrous acid in acidic medium to give 5-aminotetrazole via the intermediate guanylazide. [14] At neutral pH, the reaction leads to tetrazene. [17] Diazotization in acetic acid yields 1,3-di-(tetrazolyl)-triazene. [14]

5-Aminotetrazole synthesis01.svg

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References

  1. ↑ Thornalley, Paul J. (2003). "Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts". Archives of Biochemistry and Biophysics. 419 (1): 31–40. doi:10.1016/j.abb.2003.08.013. PMID   14568006.
  2. ↑ "Synvista Therapeutics Inc. - BioCentury Company Profiles - BCIQ". BioCentury. Retrieved 2023-05-30.
  3. 1 2 "Alteon 10-K For the fiscal year ended December 31, 1996". Alteon via SEC Edgar. March 27, 1997.
  4. 1 2 Harry Keen; JH Fukker; G Menzinger (July 19, 1997). "Early closure of European Pimagedine trial". The Lancet. 350 (9072). PlumX Metrics: 214–215. doi:10.1016/S0140-6736(97)26029-0. PMID   9250200. S2CID   54316555.
  5. ↑ Barbara Marsh (January 3, 1998). "Biotech's New Watchword: Partnership". Los Angeles Times. Retrieved August 17, 2017.
  6. ↑ "Alteon May Drop Pimagedine In NIDDM". The Pharma Letter. March 19, 1998. Retrieved August 17, 2017.
  7. ↑ "Alteon Shares Plummet On Poor Pimagedine Test Results". San Diego Source. November 16, 1998. Retrieved August 17, 2017.
  8. ↑ http://business.globe24h.com/sec/001/06/060000/0000060271.shtml [ dead link ]
  9. ↑ "Alteon's pimagedine fails primary endpoint". The Pharma Letter. April 12, 1999. Retrieved August 17, 2017.
  10. ↑ https://www.sec.gov/Archives/edgar/data/878903/0000893220-00-000381.txt [ bare URL plain text file ]
  11. ↑ https://www.sec.gov/Archives/edgar/data/878903/000089322001000240/0000893220-01-000240.txt [ bare URL plain text file ]
  12. ↑ https://www.sec.gov/Archives/edgar/data/878903/000089322002000222/0000893220-02-000222.txt [ bare URL plain text file ]
  13. ↑ https://www.sec.gov/Archives/edgar/data/878903/000089322003000272/0000893220-03-000272.txt [ bare URL plain text file ]
  14. 1 2 3 4 Güthner, Thomas; Mertschenk, Bernd; Schulz, Bernd (2006), "Guanidine and Derivatives", Ullmann's Encyclopedia of Industrial Chemistry, American Cancer Society, doi:10.1002/14356007.a12_545.pub2, ISBN   978-3-527-30673-2
  15. ↑ Smith, G. B. L.; Anzelmi, Edward (1935-12-01). "Reduction of Nitroguanidine. III. Synthesis of Aminoguanidine1". Journal of the American Chemical Society. 57 (12): 2730. Bibcode:1935JAChS..57.2730S. doi:10.1021/ja01315a510. ISSN   0002-7863.
  16. ↑ Adams, J. M. (1977). "The Crystal Structure of Aminoguanidinium Dihydrogen Orthophosphate". Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry. 33 (5): 1513–1515. Bibcode:1977AcCrB..33.1513A. doi:10.1107/S0567740877006402.
  17. ↑ Patinkin, Seymour H.; Horwitz, Jerome P.; Lieber, Eugene (1955-02-01). "The Structure of Tetracene1,2". Journal of the American Chemical Society. 77 (3): 562–567. Bibcode:1955JAChS..77..562P. doi:10.1021/ja01608a014. ISSN   0002-7863.
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