O'Really?

March 4, 2010

Sildenafil citrate: Entity of the Month

30 St Mary Axe or the Gherkin - London by Patrick MayonRelease 66 of Chemical Entities of Biological Interest (ChEBI) is now available, containing 534,521 total entities, of which 20,151 are annotated entities and 698 were submitted via the ChEBI submission tool. This months entity of the month is Viagra, also known as Sildenafil citrate: (Text below reproduced from ChEBI website)

Few chemical compounds are better known to the general public than sildenafil citrate (CHEBI:58987), traded under the name of “Viagra”.The compound was first synthesised by chemists working at Pfizer, with a view to using it for the treatment of hypertension and angina pectoris. Whilst having been found to be ineffective against angina in clinical trials, it has been observed to induce penile erections and was therefore marketed by Pfizer as a drug for the treatment of erectile dysfunction.

A number of synthetic routes for the preparation of the parent sildenafil have been reported [1]. A common industrial synthetic route is through reaction of 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide and 2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylbenzoic acid followed by subsequent cyclisation to sildenafil through heating under acidic conditions.

Sildenafil has been shown to be an inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5, an enzyme which is responsible for the degradation of 3′,5′-cyclic GMP (cyclic guanosine monophosphate, cGMP) in the corpus cavernosum. This leads to the presence of increased levels of cGMP, which, in turn causes vasodilation of the helicine arteries and thus increased blood flow into the spongy tissue of the penis [2].

Apart from the treatment of sexual dysfunction, sildenafil is also used in the treatment of pulmonary arterial hypertension and works again through relaxation of the arterial wall, which leads to a decrease in arterial resistance [3]. Furthermore – and arguably most interestingly – sildenafil has been found to decrease the time necessary for the re-entrainment of circadian rhythms after phase advances in the light–dark cycle (such as occur on transmeridian eastbound flights) in members of the Cricetidae family [4]*. The discovery was rewarded with the award of an Ig Nobel Prize in Aviation in 2007.

* or as wikipedia puts it…”Viagra aids jet lag recovery in hamsters” …that’s an interesting side effect.

References

  1. Dunn, P. (2005). Synthesis of Commercial Phosphodiesterase(V) Inhibitors Organic Process Research & Development, 9 (1), 88-97 DOI: 10.1021/op040019c
  2. Webb DJ, Freestone S, Allen MJ, & Muirhead GJ (1999). Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. The American journal of cardiology, 83 (5A) PMID: 10078539
  3. Richalet, J. (2004). Sildenafil Inhibits Altitude-induced Hypoxemia and Pulmonary Hypertension American Journal of Respiratory and Critical Care Medicine, 171 (3), 275-281 DOI: 10.1164/rccm.200406-804OC
  4. Agostino, P., Plano, S., & Golombek, D. (2007). Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules Proceedings of the National Academy of Sciences, 104 (23), 9834-9839 DOI: 10.1073/pnas.0703388104

[Creative Commons licensed picture of 30 St Mary Axe or the Gherkin – London by Patrick Mayon, see comments on this post at friendfeed]

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