PDE5 inhibitors

The PDE5 compounds also are susceptible to pharmacokinetic interactions caused by drugs that induce or inhibit their metabolism. Although published data are limited, the PDE5 agents all appear to be primarily metabolized by cytochrome P-450 3A4. In addition, sildenafil and perhaps vardenafil are metabolized by CYP2C9, although to a minor extent.4 Furthermore, vardenafil metabolism has been reported to be mediated by CYP3A5, an enzyme closely related to CYP3A4.

Moreover, the PDE5 drugs differ in some of their pharmacokinetic parameters. Sildenafil and vardenafil have half-lives of 4 to 5 hours, whereas the half-life of tadalafil is ~17 hours. The bioavailability of sildenafil is reported to be 40%, and that of vardenafil is 15%; however, the bioavailability of tadalafil has not been reported.

Phosphodiesterase type 5 (PDE5) is responsible for the metabolic degradation of cyclic guanosine monophosphate (cGMP). Inhibition of PDE5 will lead to increased levels of cGMP. Organic nitrates exert their action by activation of guanylate cyclase, which also increases levels of cGMP. The concurrent use of these two drugs could lead to an excessive increase of cGMP resulting in excessive hypotensive effects.

Part of the physiological process of erection involves the release of nitric oxide (NO) in vasculature of the corpus cavernosum as a result of sexual stimulation. NO activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum, resulting in increased inflow of blood and an erection.

PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type 5 (PDE5), increasing bloodflow to the penis during sexual stimulation. This mode of action means that PDE5 inhibitors are ineffective without sexual stimulation.

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.