Sildenafil Viagra

Ball-and-Stick Model

= Hydrogen

Nitrogen

= Sulfur

Year of discovery: 1989; Year of introduction: 1998 (Pfizer); Drug category: Selective inhibitor of cGMP specific type 5 phosphodiesterase; Main uses: Treatment of male erectile dysfunction and pulmonary arterial hypertension; Related drugs: Tadalafil (Cialis), Vardenafil (Levitra); Other brand names: Revatio.

Sildenafil, the first selective type 5 phosphodiesterase inhibitor (PDE-5), is an effective oral treatment for erectile dysfunction, a condition that affects about 30 million men in the US. It is also efficacious for pulmonary artery hypertension caused by narrowed arteries in the lung. This condition results in a reduced supply of oxygen in the body (ischemia) and multiple consequences, including damage to the heart.'

The development of sildenafil as a potent therapy for erectile dysfunction was the result of a serendipitous discovery during research to identify phosphodiesterase (PDE) enzyme inhibitors for the treatment of high blood pressure and angina at Pfizer. One of the candidate molecules, UK92480, later called sildenafil, exhibited highly selective inhibitory activity against type 5 phosphodiesterase. It was observed clinically that although sildenafil is not efficacious for the treatment of angina, it markedly increases erectile function. Clinical trials of sildenafil for the treatment of erectile dysfunction began in 1993 and led to approval in 1998. Sildenafil, marketed as a citrate salt under the name Viagra, soon became a billion-dollar drug. In the late 1990s it was recognized that sildenafil is beneficial for the treatment of pulmonary artery hypertension. It is available for this indication since 2005 under the name Revatio.2

The physiological process of erection is initiated by the release of nitric oxide (NO), a short-lived neurotransmitter that activates the enzyme guanylate cyclase, leading to increased production of cyclic guanosine monophosphate (cGMP). cGMP triggers a cascade of biochemical processes that results in vasodilation in the corpus cavernosum. increased penile blood flow and erection. This process is reversed by type 5 phospho diesterase, which catalyzes the conversion of cGMP GMP).

to guanosine monophosphate (5'-

type 5 phospho-

cGMP

Sildenafil increases cGMP levels and improves erectile function. Sildenafil does not affect the production of cGMP and has no effect in the absence of sexual stimulation.

The beneficial effect of sildenafil in pulmonary arterial hypertension is due to the elevated levels of type 5 phosphodiesterase in the pulmonary arterial walls of hypertensive individuals.3,1

Binding of sildenafil to type 5 phosphodiesterase.

Two additional PDE-5 inhibitors, vardenafil (Levitra™, Bayer) and tadalafil (Cialis™, Eli Lilly) were introduced in 2003.

Vardenafil (Levitra

1. Nature 2003, 425, 98-102 (1UDT); 2. Nat. Rev. Drug Discov. 2006, 5, 689-702; 3. N. Engl. J. Med. 2000, 342. 1802-1813; Refs. p. 105

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