Pimagedine, also known as aminoguanidine, is an investigational

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhala ...

for the treatment of

diabetic nephropathy Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease ...

that is no longer under development as a drug. Pimagedine functions as an

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

diamine oxidase Diamine oxidase (DAO), also known "amine oxidase, copper-containing, 1" (AOC1), formerly called histaminase, is an enzyme () involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermid ...

and

nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and perist ...

. It acts to reduce levels of

advanced glycation end product Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, ath ...

s (AGEs) through interacting with 3-deoxyglucosone,

glyoxal Glyoxal is an organic compound with the chemical formula OCHCHO. It is the smallest dialdehyde (a compound with two aldehyde groups). It is a crystalline solid, white at low temperatures and yellow near the melting point (15 °C). The li ...

methylglyoxal Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a reactive compound that is implicated in the biology of diabetes. Methylglyoxal is produced industrially by degradation ...

, 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. In 1987, Alteon acquired a license to intellectual property relating to AGE inhibition from Rockefeller University. In 1989, Alteon and Marion Merrell Dow Inc (MMD) entered into a joint development program for pimagedine. 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. 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. 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." In February, 1999, Genentech ended its collaboration with Alteon to develop pimagedine. 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. Alteon's 2000, 2001, 2002 annual reports indicated that it was not running any clinical trials on pimagedine but was seeking co-development partners.https://www.sec.gov/Archives/edgar/data/878903/0000893220-00-000381.txt Alteon's 2003 and subsequent annual reports did not mention that Alteon was seeking partners for pimagedine, 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.

Chemistry

Synthesis

The industrial synthesis uses the reaction between

cyanamide Cyanamide is an organic compound with the formula C N2 H2. This white solid is widely used in agriculture and the production of pharmaceuticals and other organic compounds. It is also used as an alcohol-deterrent drug. The molecule features a ...

and

hydrazine Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...

in aqueous solution. : The compound can also be obtained from the reduction of

nitroguanidine Nitroguanidine - sometimes abbreviated NGu - is a colorless, crystalline solid that melts at 257 °C and decomposes at 254 °C. Nitroguanidine is an extremely insensitive but powerful high explosive. Wetting it with > 20 wt.-% water effe ...

with

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main componen ...

Properties

Aminoguanidine forms a colorless crystal that is soluble in water and ethanol. It is basic, producing salts when reacted with organic acids. With formic acid, a cyclization takes place to give

3-amino-1,2,4-triazole 3-Amino-1,2,4-triazole (3-AT) is a heterocyclic organic compound that consists of a 1,2,4-triazole substituted with an amino group. 3-AT is a competitive inhibitor of the product of the HIS3 gene, imidazoleglycerol-phosphate dehydratase. Imidazol ...

. : The compound reacts with

nitrous acid Nitrous acid (molecular formula ) is a weak and monoprotic acid known only in solution, in the gas phase and in the form of nitrite () salts. Nitrous acid is used to make diazonium salts from amines. The resulting diazonium salts are reagent ...

in acidic medium to give 5-aminotetrazole via the intermediate guanylazide. At neutral pH, the reaction leads to

tetrazene Tetrazene is a chemical compound with the molecular formula H2NN=NNH2. It is a colorless explosive material. An analogue is the organosilicon derivative (tms)2NN=NN(tms)2 where tms is trimethylsilyl. Isomeric with tetrazine is ammonium azide. T ...

Diazotization Diazonium compounds or diazonium salts are a group of organic compounds sharing a common functional group where R can be any organic group, such as an alkyl or an aryl, and X is an inorganic or organic anion, such as a halide. General propert ...

yields 1,3-di-(tetrazolyl)-triazene. :

References

{{Hydrazines Guanidines Hydrazines