Sildenafil The Blue and White Pill By Verity Jane Litchfield

1. Sildenafil The Blue and White Pill By Verity Jane Litchfield Revatio Revatio is the same active pharmaceutical ingredient sildenafil citrate but it is used in the treatment for the rare disease pulmonary arterial hypertension (PAH). It works with the same mechanism as Viagra for relaxing the smooth muscle. In this case relaxes the arterial wall leading to decreased pulmonary arterial resistance and pressure this leads to a reduction in the workload of the right ventricle and improves symptoms of right-sided heart failure. The FDA approved Revatio for use for PAH in 2005. Synthesis of Sildenafil Sildenafil citrate more commonly known as Viagra the erectile dysfunction (ED) treatment but also marketed as Revatio a treatment for pulmonary arterial hypertension (PAH). • Viagra: • Viagra well known because of its appearance it is used to treat Erectile Disfunction. It was developed and marketed by Pfizer after seen as a side affect in clinical trials for hypertension (high blood pressure). It works by inhibiting cGMP specific phosphodiesterase type 5 an enzyme that regulates the blood flow in the penis. • Mechanism of action: • Sexual stimulation causes increased release of nitric oxide (NO) from non-cholinergic, non-adrenergic parasympathetic nerve (NANC) endings in the walls of the arteries and sinusoids of the penile corpora cavernosa. Nitric oxide diffuses into the vascular smooth muscle cells of the walls of the arteries and sinusoids and stimulates cytoplasmic guanylyl cyclase to increase cGMP production. Increased levels of the cGMP cause the relaxation of the smooth muscle cells supplying the corpus cavernosum with blood. This increases the blood flow to the penis and expansion of the corpus cavernosa, which restricts the outflow of venous blood resulting in an erection from the pressure in blood. • Since PDE5 is the principle enzyme responsible for the decomposition of cGMP in the corpus cavernosum, it is reasonable to expect that inhibition of it results in the increase of cGMP concentration, leading to enhanced smooth muscle relaxation and improvement in erections Unlike Viagra which is used in 25, 50 and 100mg in occasional doses, Revatio is dosed in 20mg amounts to be taken three times a day as it only has a half life in the body of four hours. It comes as small white round tablets unlike Viagra's well known colour blue and also can be administrated via injection. Competition: There is always competition from other companies as in 2000 the annual sales exceeded $1 billion dollars and accounted for 92 percent of ED sales in 2007. This percentage dropped due a few factors including the main compeptitors are Tadalafil (Cialis) and Vardenafil (Levitra) entering the market and counterfeits. Tadalafil trade name Cialis is known as the weekend drug as it can be effective for up to 36 hours as its half life is 17.5 hours and only needs to be dosed at 5, 10 and 20mg. It came onto the market by Eli Lily in 2003 and also was approved in May 2009 for the treatment of PAH in a dose of 40mg called Adcirca. Tadalafil inhibits PDE6 the least compared to sildenafil and vardenafil deceasing chance of vision side affects. The first step of the synthesis is the reaction of a diketoester (1) and hydrazine to give the pyrazole ring. The regioselective N-methylation of the pyrazole and hydrolysis gives a carboxylic acid (3). Compound (3) is then reacted with HNO3 and H2SO4 to give a nitrated product. This is then followed by a carboxamide formation and the reduction of the nitro group. The compound (4) is then acylated under basic conditions and this produces the pyrazolopyrimidinone (6). (6) is then chlorosulphonylated selectively on the 5'-position of the phenyl ring. This can then couple with an amine to give sildenafil (7). Tadalafil Vardenafil trade name Levitra when sold by Bayer and sold by GSK as Vivanza. Very similar structure to sildenafil with exceptions to the nitrogens and side chains it has a longer time in the body than viagra so only needs to be dosed in 2.5, 5, 10 or 20mg doses. Vardenafil is the only one of the three not also approved for treatment for PAH also in rare cases it has been found to cause damage to the penile tissue leading to permanent impotence. Side affects: The most common side affects include headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred vision. Some users have found to see everything in tinted blue (cyanopsia). This is caused by inhibiting slightly the PDE6 which affects vision in rare cases it has lead to vision impairment. Other side affects in rare amounts include heart attacks, stroke, severe hypertension and sudden loss of hearing. Vardenafil References used for Information include: Medicinal Research Reviews, Vol. 26, No. 3, 369-395, 2006; Nature Reviews, Drug Discovery, Vol. 5, Aug 2006; Bioorganic and Medicinal Chemistry Letters, Vol.6, No. 15, pp. 1819-1824, 1996; Pfizer web pages; Wikipedia Nanc nerves Nitric oxide Activation of guanylyl cyclase First published case report on the successful treatment of one patient with primary PAH with chronic administration of Sildenafil PDE5 Sildenafil not further developed for cardiovascular indications because of relatively short life and potential interactions with nitrates Approval of Silenafil as Viagra by FDA as first oral treatment for ED Sildenafil selected as candidate drug to enter clinical development for Cardiovascular indications Nitric Oxide was described as a neurotransmitter that’s released during sex. Synthesis of cGMP Decomposition of cGMP to 5’-GMP End of Pfizer’s Viagra Patent 1986 1989 1990 1993 1998 2000 2005 2011-2013 Smooth muscle relaxation Between ‘91 and 2000 research reports the potential role of PDE5 in the lungs vasculature: first experimental use of other PDE5 inhibitors in experimental model of PAH. First studies in ED proving efficiency in single doses of sildenafil in enhancing erectile responses during sexual stimulation First Intravenous placebo-controlled study evaluating effect of different doses of sildenafil for PAH patients Formation of Research team at Pfizer for selective PDE5 inhibitor Approval of Sildenafil as Ravatio for the treatment of PAH by FDA and by the EMEA. Increase of blood flow in corpus cavernosum Erection

2. Omeprazole: A Case Study 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole Introduction Synthesis/Manufacture Physical Properties Omeprazole is a highly effective compound that inhibits gastric acid secretion and is indicated in the treatment of acid-related disorders such as Gastroesophageal Reflux Disease (GERD), peptic ulcers and Zollinger-Ellison syndrome. Unlike the histamine H2-receptor antagonists, such as Cimetidine, Omeprazole works by inhibiting the H+K+ATPase in the proton pump of the gastric parietal cells. • Lipophilic - Easily penetrates cell membranes • Weak base - Concentrates in acidic compartments of parietal cell • Unstable in acidic solution – Readily converts to active species • Half life (Olbe, 2003) • At pH1 ~ 2 minutes • At pH7.4 ~ 20 hrs • Blood plasma = 1-2 hrs • Site of action ~ 24 hrs Lead Generation Astra was interested in developing an antisecretory drug and a search of the literature in 1972 discovered the compound CMN 131 (by Servier) (Figure 1). However the compound showed severe acute toxicity. Astra believed the thioamide group to be responsible. Safety/Toxicology The thioamide group was eliminated by incorporating it between heterocyclic rings and the first hit showed no acute toxicity. The product was benzimidazole H124/26 (Figure 2). • The MSDS data for Omeprazole shows that it is an irritant to the skin, respiratory organs and the eyes. • Drug interactions: • Drugs for which gastric pH can affect bioavailability (Ketoconazole, Digoxin) • Drugs metabolized by cytochrome P450 (CYP) • Drugs eliminated by the liver (Warfarin, Diazepam, Phenytoin) H124/26 was found to be under a Hungarian patent. The sulphoxide metabolite H83/69 was found to be even more potent and was not covered by the patent. The new lead compound was named Timoprazole (Figure 3). Figure 5: Synthesis of omeprazole (Saunders, 2000) Mode of Action In long term toxicological studies Timoprazole was found to cause enlargement of the thyroid gland due to inhibition of Iodine uptake. Further testing found compound H149/94 which showed antisecretory action without effects on the thyroid. The new lead compound was named Picoprazole (Figure 4). In order to suppress gastric acid secretion, Omeprazole forms a stable disulfide bond with the sulfhydryl group of the H+K+ATPase this prevents the final transport of hydrogen ions (via exchange with potassium ions) into the gastric lumen. Conclusion Omeprazole is a racemate composed of a 1:1 mixture of R and S isomers. Further research at AstraZeneca looked at many variations of the substituted benzimidazole and only one compound showed greater activity than Omeprazole. This was one of its optical isomers – the S isomer or Esomeprazole. A lot of research is currently being carried out into the effects of long term use of proton pump inhibitors including omeprazole. It is hypothesised that extended use of PPIs leads to a decrease in bone density due to reduced calcium uptake from the small intestine (Bratanic, 2009). Figure 1: CMN 131 Figure 2: H 124/26 Figure 4: Picoprazole Figure 3: Timoprazole Lead Optimisation References In order to maximise accumulation of the drug within the parietal cells, substituents were added to the pyridine ring of Timoprazole., The resulting compound was H 168/68 named Omeprazole. This compound increased the rate of conversion to the active species and is more stable to conversion at neutral pH in comparison to Picoprazole. Bratanic, A. Kokic, S. Hozo, I. Barisic, I. Kokic, V. Long-term therapy with proton pump inhibitors is associated with decreased bone density. Medical Hypotheses. (2009). 72. 608-609 Olbe, L. Carlsson, E. Lindberg, P. A proton pump inhibitor expedition: The case histories of Omeprazole and esomeprazole. Nature. (2003). 2. 132-139 Saunders, J. 2000. Top Drugs: Top Synthetic Routes. US: Oxford University Press Figure 6: Proton pump inhibition (Olbe, 2003) Jo-Ann Daniells – N0099034 Advanced Medicinal Chemistry 11 March 2014