Sildenafil (Viagra)University of California of San Diego

Author’s Note

This group final paper was written for Dr. James Whitesell’s Chemistry 151: Molecules that Changed the World, Winter 2013.

Abstract/Introduction

It was 1995 and Charles Hancock, a 65 year old male with diabetes, had recently begun experiencing difficulties in the bedroom. That is, he could not get it up. He explained to his wife and the doctor that he was still very sexually aroused by the love of his life, Mary, for 30 years, but could not seem to get his penis erect like he used to when he was in his prime. One year later, Charles’ sex life, unbeknownst to him, would be saved with a miracle drug called Viagra.

Figure 1. Sildenafil Citrate

Sildenafil Citrate(Figure 1.), popularly known for its trade name Viagra and Revatio, was synthesized at Pfizer in England. Initially, Sildenafil was studied for its effects in hypertension (high blood pressure) and angina pectoris (chest pain due to ischemic heart disease). During phase 1 clinical trials, it was observed that Sildenafil did not have any significant effects on angina; however, it was noted that it induced penile erections. However, it is now used to treat various conditions including pulmonary arterial hypertension, high blood pressure, high-altitude pulmonary edema, jet lag and vasculogenic impotence. This breakthrough for erectile dysfunction led to Pzifer’s patent and approval in the United States in 1996.

In recent statistics, approximately 30 million males in the United States of America are battling different severities of erectile dysfunction. Women alike can suffer the same condition as men resulting in an insufficient blood flow to the clitoris. But treated with Sildenafil, women too could rectify the dysfunction. With minimal side effects such as flushing, congestion, headache, blurred vision, priapism of up to seven hours, Viagra is only effective with sexual arousal and does not increase sexual drive or libido as some may think. Another myth of Viagra is that is the

source of erectile dysfunction. Many origins of erectile dysfunction are actually caused by diabetes, drug use, vascular disease, hormone disorders, neurologic disorders, pelvic trauma, radiation exposure, venous sleep, psychological problems and /or Pyrenees disease and not just impotence. Thus, a multi-billion dollar market worldwide of Viagra emerged.

Biological Mechanism

***Notes on whole section: This section is not very useful, unless you are going to compare/contrast it to the mechanism of Viagra and how it affects the

biology. Either add the effect to show where/how Viagra is effective or remove entire section***

On a normal physiological scale, an erection would start with sexual stimulation that would trigger a release of neurotransmitters from the cavernous nerve in the endothelial cell. This allows relaxation of smooth muscles from the release of nitric oxide. The nitric oxide is released in the smooth muscles causing a dilation of arteries to increase the blood flow through the penile walls. In detail:

1. Dilatation of the arterioles and arteries by increased blood flow in both the diastolic and the systolic phases

2. Trapping of the incoming blood by the expanding sinusoids3. Compression of the subtunical venular plexuses between the tunica

albuginea and the peripheral sinusoids, reducing the venous outflow4. Stretching of the tunica to its capacity, which occludes the emissary

veins between the inner circular and the outer longitudinal layers and further decreases the venous outflow to a minimum

5. An increase in PO2 (to about 90 mmHg) and intracavernous pressure (around 100 mm Hg), which raises the penis from the dependent position to the erect state (the full-erection phase)

6. A further pressure increase (to several hundred millimeters of mercury) with contraction of the ischiocavernosus muscles (rigid-erection phase)

Smooth muscle contraction and relaxation are regulated by cytosolic (sarcoplasmic) free Ca2+. Norepinephrine from nerve endings and endothelins and prostaglandin F2α from endothelium activate receptors on smooth muscle cells to increase inositol triphosphate and diacylglycerol resulting in release of calcium from intracellular stores such as sarcoplasmic reticulum and/or opening of calcium channels on the smooth muscle cell membrane leading to an influx of calcium from extracellular space. This triggers a transient increase in cytosolic free Ca2+ from a resting level of 120 to 270 to 500 to 700 nM.32At the elevated level, Ca2+ binds to calmodulin and changes the latter’s conformation to expose sites of interaction with myosin light-chain kinase. The resultant activation catalyzes phosphorylation of myosin light chains and triggers cycling of myosin crossbridges (heads) along actin filaments and the development of force. In addition, phosphorylation of the light chain also activates myosin ATPase, which hydrolyzes ATP to provide energy for muscle contraction. In other words, free Ca2+ continues the erection state until natural dissipation through an enzymatic breakdown by phosphodiesterase type 5 from cGMP into GMP. Viagra acts on this mechanism by blocking the phosphodiesterase type 5 allowing the free Ca2+ to continue the muscles relaxation for longer until the Sildenafil decays.

*going into too much detail, without showing the importance of knowing this much.

Commercial Synthesis of Sildenafil

***Is this level of detail necessary for the description of Viagra?***

The preparation steps for synthesis of sildenafil are as follows: 1. Methylation of 3-

propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfateHydrolysis with aqueous NaOH to free acid

2. Nitration with oleum/fuming nitric acid

3. Carboxamide formation with refluxing thionyl chloride/NH4OH

4. Reduction of nitro group to amino

5. Acylation with 2-ethoxybenzoyl chloride

6. Cyclization7. Sulfonation to the

chlorosulfonyl derivative8. Condensation with 1-

methylpiperazine.

Figure 1: Commercial Synthesis of Sildenafil

Charles Hancock continued his marriage no longer sexually frustrated but happy, satisfied, and with an orange prescription bottle for Viagra next to his bed.

References

Dean, Richard. "Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction." Http://www.ncbi.nlm.nih.gov/. Urologic Clinics of North America, 25 Jan. 2006. Web. 7 Feb. 2014.

 Dunn, Peter J. "Synthesis of Commercial Phosphodiesterase(V) Inhibitors." Organic Process Research & Development 9.1 (2005): 88-97.

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