pimagedine
{{Chembox
|Verifiedfields = changed
|Watchedfields = changed
|verifiedrevid = 403348066
|ImageFileL1 = Aminoguanidin.svg
|ImageFileL1_Ref = {{chemboximage|correct|??}}
|ImageNameL1 = Skeletal formula of a pimagedine
|ImageFileR1 = Aminoguanidine sf.png
|ImageFileR1_Ref = {{chemboximage|correct|??}}
|ImageNameR1 = Spacefill model of a pimagedine
|IUPACName = 2-Aminoguanidine
|OtherNames = {{Unbulleted list|Aminoguanidine|Guanyl hydrazine|Hydrazinecarboximidamide|Imino semicarbazide|Monoaminoguanidine}}
|Section1 = {{Chembox Identifiers
|IUPHAR_ligand = 5135
|CASNo = 79-17-4
|CASNo_Ref = {{cascite|correct|CAS}}
|PubChem = 2146
|ChemSpiderID = 2061
|ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
|UNII = SCQ4EZQ113
|UNII_Ref = {{fdacite|changed|FDA}}
|ChEMBL = 225304
|ChEMBL_Ref = {{ebicite|correct|EBI}}
|KEGG = D05479
|SMILES = NC(N)N=N
|StdInChI = 1S/CH6N4/c2-1(3)5-4/h1,4H,2-3H2
|StdInChI_Ref = {{stdinchicite|changed|chemspider}}
|StdInChIKey = DRCHNMARIZRTKI-UHFFFAOYSA-N
|StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
}}
|Section2 = {{Chembox Properties
|C=1 | H=6 | N=4
|LogP = −1.475
|Density = 1.72 g/ml
|MolarMass = 74.085 g/mol
|BoilingPtC = 261
}}
|Section3 = {{Chembox Related
|OtherCompounds = Guanidine}}
}}
Pimagedine, also known as aminoguanidine, is an investigational drug for the treatment of diabetic nephropathy that is no longer under development as a drug.{{cite journal|doi=10.1016/j.abb.2003.08.013|title=Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts|year=2003|last1=Thornalley|first1=Paul J.|journal=Archives of Biochemistry and Biophysics|volume=419|issue=1|pages=31–40|pmid=14568006}} 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.
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.{{Cite web |title=Synvista Therapeutics Inc. - BioCentury Company Profiles - BCIQ |url=https://profiles.biocentury.com/companies/synvista_therapeutics_inc |access-date=2023-05-30 |website=BioCentury}} In 1987, Alteon acquired a license to intellectual property relating to AGE inhibition from Rockefeller University.{{cite web|title=Alteon 10-K For the fiscal year ended December 31, 1996|url=https://www.sec.gov/Archives/edgar/data/878903/0000893220-97-000614.txt|publisher=Alteon via SEC Edgar|date=March 27, 1997}} In 1989, Alteon and Marion Merrell Dow Inc (MMD) entered into a joint development program for pimagedine.{{cite journal|url=http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)26029-0/fulltext|author=Harry Keen|author2=JH Fukker|author3=G Menzinger|title=Early closure of European Pimagedine trial|journal=The Lancet|publisher=PlumX Metrics|volume=350|issue=9072|pages=214–215|date=July 19, 1997|doi=10.1016/S0140-6736(97)26029-0|pmid=9250200|s2cid=54316555|url-access=subscription}} In 1992, Alteon licensed a patent from Rockefeller University relating to the use of pimagedine to inhibit AGE formation. 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. 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.{{cite news|url=https://www.latimes.com/archives/la-xpm-1998-jan-03-fi-4444-story.html | work=Los Angeles Times|author=Barbara Marsh|title=Biotech's New Watchword: Partnership|date=January 3, 1998|access-date=August 17, 2017}}
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.{{cite web|url=http://www.thepharmaletter.com/file/19466/alteon-may-drop-pimagedine-in-niddm.html|title=Alteon May Drop Pimagedine In NIDDM|publisher=The Pharma Letter|date=March 19, 1998|access-date=August 17, 2017}} 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."{{cite news|url=http://www.sddt.com/News/article.cfm?SourceCode=19981116faq|title=Alteon Shares Plummet On Poor Pimagedine Test Results|publisher=San Diego Source|date=November 16, 1998|access-date=August 17, 2017}} In February, 1999, Genentech ended its collaboration with Alteon to develop pimagedine.{{Cite web | url=https://www.thepharmaletter.com/genentech-pulls-out-of-pimagedine-deal | title=Genentech pulls out of pimagedine deal | date=1999-02-10 | website=www.thepharmaletter.com}} 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.{{cite web|url=http://www.thepharmaletter.com/file/71571/alteons-pimagedine-fails-primary-endpoint.html|title=Alteon's pimagedine fails primary endpoint|publisher=The Pharma Letter|date=April 12, 1999|access-date=August 17, 2017}} Alteon's 2000, 2001, 2002 annual reports indicated that it was not running any clinical trials on pimagedine but was seeking co-development partners.{{Cite web | url=https://www.sec.gov/Archives/edgar/data/878903/0000893220-00-000381.txt | format=TXT | title=ALTEON, INC. FORM 10-K | date=2000-03-31}}{{Cite web | url=https://www.sec.gov/Archives/edgar/data/878903/000089322001000240/0000893220-01-000240.txt | format=TXT | title=FORM 10-K ALTEON INC. | date=2001-03-07}}{{Cite web| title=ALTEON INC. FORM 10-K FOR FISCAL YEAR END 12/31/01 | url=https://www.sec.gov/Archives/edgar/data/878903/000089322002000222/0000893220-02-000222.txt | archive-url=https://web.archive.org/web/20130313201923/http://www.sec.gov/Archives/edgar/data/878903/000089322002000222/0000893220-02-000222.txt | archive-date=2013-03-13}} Alteon's 2003 and subsequent annual reports did not mention that Alteon was seeking partners for pimagedine,{{Cite web| title=Form 10-K for Alteon Inc. | url=https://www.sec.gov/Archives/edgar/data/878903/000089322003000272/0000893220-03-000272.txt | archive-url=https://web.archive.org/web/20130313201919/http://www.sec.gov/Archives/edgar/data/878903/000089322003000272/0000893220-03-000272.txt | archive-date=2013-03-13}} 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|date=February 2021}}
Chemistry
= Synthesis =
The industrial synthesis uses the reaction between cyanamide and hydrazine in aqueous solution.{{Citation|last1=Güthner|first1=Thomas|title=Guanidine and Derivatives|date=2006|encyclopedia=Ullmann's Encyclopedia of Industrial Chemistry|publisher=American Cancer Society|language=en|doi=10.1002/14356007.a12_545.pub2|isbn=978-3-527-30673-2|last2=Mertschenk|first2=Bernd|last3=Schulz|first3=Bernd}}
:File:Aminoguanidine_synthesis01.svg
The compound can also be obtained from the reduction of nitroguanidine with zinc in acetic acid.{{Cite journal|last1=Smith|first1=G. B. L.|last2=Anzelmi|first2=Edward|date=1935-12-01|title=Reduction of Nitroguanidine. III. Synthesis of Aminoguanidine1|journal=Journal of the American Chemical Society|volume=57|issue=12|pages=2730|doi=10.1021/ja01315a510|bibcode=1935JAChS..57.2730S |issn=0002-7863}}
= 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.{{cite journal |doi=10.1107/S0567740877006402|title=The Crystal Structure of Aminoguanidinium Dihydrogen Orthophosphate |year=1977 |last1=Adams |first1=J. M. |journal=Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry |volume=33 |issue=5 |pages=1513–1515 |bibcode=1977AcCrB..33.1513A }} With formic acid, condensation occurs, leading to cyclization to give 3-amino-1,2,4-triazole.
The compound reacts with nitrous acid in acidic medium to give 5-aminotetrazole via the intermediate guanylazide. At neutral pH, the reaction leads to tetrazene.{{Cite journal|last1=Patinkin|first1=Seymour H.|last2=Horwitz|first2=Jerome P.|last3=Lieber|first3=Eugene|date=1955-02-01|title=The Structure of Tetracene1,2|journal=Journal of the American Chemical Society|volume=77|issue=3|pages=562–567|doi=10.1021/ja01608a014|bibcode=1955JAChS..77..562P |issn=0002-7863}} Diazotization in acetic acid yields 1,3-di-(tetrazolyl)-triazene.
