Sildenafil development

Even on a relatively small subset of reused data, it is possible to license old medicines for new therapeutic applications and greatly reduce the costs of clinical development—many of these reused medicines have already passed muster for pharmacokinetic safety, so smaller-scale clinical trials are possible, saving considerable money (e.g., Arakis—soon to become Sosei). Even Sildenafil may have new indications [39]. There are huge potential reserves of information to mine in each and every large pharmaceutical company ... 

A patient with no history of prior disease and taking sildenafil might develop which of the following adverse effects ... 

Sildenafil and vardenafil decrease systolic/diastolic blood pressure by 8 to 10/5 to 6 mm Hg for 1 to 4 hours after a dose. Although most patients are asymptomatic, multiple antihypertensives, nitrates, and baseline hypotension increase the risk of developing adverse effects. Although tadalafil does not decrease blood pressure, it should be used with caution in patients with cardiovascular disease because of the inherent risk associated with sexual activity. 

Sildenafil was developed. However, there are different types of PDEs (nine are known today). As discussed previously, a potent drug has to be specific. Sildenafil inhibits PDE-5, which is absent in the kidney, although sildenafil s effect on smooth muscle relaxation was confirmed. The direction of the drug changed to treating angina instead, as sildenafil relaxes the vascular muscle of the heart. 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Following the development of the test, an in-house validation was conducted to evaluate the performance of FETAX compared to the results in the rat and/or rabbit. Thirteen reference chemicals were tested including eight compounds known to be teratogenic in rats and/or rabbits (caffeine, retinoic acid, hydroxyurea, ethanol, cyclophosphamide, nicotine, acetylsalicylic acid, dexametha-sone) and five non-teratogens (isoniazid, saccharin, paracetamol, penicillin G, sildenafil). The estimation of teratogenicity in rats and rabbits was based on published data (9). 

Liquid chromatography-electrospray ionization mass spectrometry (LC-ESTMS) for analysis of sildenafil has also been developed and applied to 40 botanical products. About half of the analyzed samples proved to contain undeclared additives of the three drugs sildenafil, vardenafil, and tadalafil <2004JPBA525>. A similar electrokinetic capillary chromatography method to that proposed for the determination of sildenafil 82 has been reported for vardenafil 98 and tadalafile 99. Statistical evaluation of the electrophoretic results was achieved. The described method is thought to be rapid and sensitive <2004JCH231>. 

The development of an environmentally benign synthesis of sildenafil citrate (Viagra ) and its assessment by green chemistry metrics. Green Chem. 6 (1) 43-48. 

Pfizer also received a Crystal Faraday Award for optimizing the process used to manufacture the active ingredient in Viagra , sildenafil citrate. Shown in Figure 3.6 is the solvent usage during each stage of process development for sildenafil citrate over a 15-year lime line [19]. 

The initial medicinal chemistry route for the early syntheses of sildenafil required -1540 kg solvent/kg API. After four years of development, a modified chemical route and process led to a 93.9% reduction in the total amount of solvent used. The continued optimization of the sildenafil process as it went into commercial production further reduced the amount of solvent used from 94 to 19 kg solvent/kg API. Several highly hazardous solvents were also eliminated from the production scheme including DCM, methanol, and diethyl ether. Upon implementation of solvent recovery, the total amount of solvent required was only 5 kg solvent/kg API produced [17, 20]. The final commercial route used only 0.32% of the total solvent used for the initial synthesis. 

Figure 3.6 Solvent usage in the development of sildenafil (adapted from data provided courtesy of P. J. Dunn, Pfizer Inc. [19]).

Dunn, P. J., Galvin, S., Hettenbach, K. The Development of an Environmentally Benign Synthesis of Sildenafil Citrate (Viagra) and Its Assessment by Green Chemistry Metrics. Green Chem. 2004, 6, 43 18. 

The chemical development of the commercial route to sildenafil also serves as an excellent example of the different issues that need to be considered when moving from drug discovery to commercial quantities. This problem is therefore based on the commercial synthesis of sildenafil as published by the Pfizer research group around P. J. Dunn ... 

The synthesis of sildenafil serves as an excellent example of the demands of commercial chemistry. The route described contains all of the desired attributes required in chemical development, namely a safe, robust route, a convergent synthesis and a high yielding process. The authors managed to improve the yield from 7.5 % in the medicinal chemistry to 75.8 % overall from pyrazole 3. The synthesis also has an exceptionally low environmental impact. Only toluene and ethyl acetate are organic waste while the other solvents (ethanol and tert-butanol) can be treated in the water plants. The synthesis has been... 

Supported reagents for the development of drug targets - Sildenafil... 

In the USA the Presidential Green Chemistry Challenge Awards [7] were introduced to stimulate the application of the principles of green chemistry and many chemical and pharmaceutical companies have received awards for the development of greener processes and products, e.g. Pfizer for developing a greener process for sildenafil manufacture (see Chapter 7). 

Sildenafil Endometrial development for embryo implantation Vaginal suppository Enhanced endometrial development was achieved 340... 

Sher, G., and Fisch, J. D. (2002), Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development, Fertil. Steril, 78,1073-1076. 

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