Sildenafil, structure

In 2005 we reported the synthesis of some sildenafil (3) analogues and their tyrosinase inhibitory potential [43]. The compoimds were synthesized using microwave irradiation in key steps, such as the SNAr reaction on important precursor bromopyrazole [44]. Their molecular structures are shown in Fig. 3. 

Fig. 3 Molecular structures of the synthesized sildenafil (3) and some of its analogues (4-7) which exhibited promising tyrosinase inhibitory activities [43]...

Since vardenafil has a very similar chemical structure to sildenafil, it is not surprising that it has a similar clinical profile. One study has reported no impairment of exercise ability in stable CAD patients receiving vardenafil 20 mg (49). Similar clinical efficiency for all three agents has been observed in patients with diabetes,... 

Fig. 1.15 Structure of the phosphodiesterase type 5 (PDES) inhibitor sildenafil [25,26].

Fig. 3.10 Structural optimization of the anti-allergic xanthines 40 and 41 led to the PDE5 inhibitor sildenafil. Whereas varde-nafil 43 is a close analogue of sildenafil, tadalafil 44 belongs to a different class of compounds both, 43 and 44, are highly potent PDE5 inhibitors.

Sildenafil (citrate), a complicated piperazine-pyrazolopyrimidine structure, vasodilator and small muscle relaxant for erectile dysfunction [139755-83-2],... 

Much earlier, a structurally different inhibitor type bearing the heterocyclic core of sildenafil appeared in the patent literature (Figure 9.31). Compound 135 is a micromolar PDE1 inhibitor, which also shows affinity for the adenosine receptor [111]. By tuning the substituents, the more potent and selective inhibitor 136 was obtained some 10 years later by the Pfizer UK group [112]. 

Sildenafil, tadalafil and vardenafil have similar, although not identical, mechanisms of action and structural similarity, and are metabolized primarily by the CYP3A4 isoenzymes, Vardenafil is 32-fold more potent than sildenafil in inhibiting phosphodiesterase type 5. Tadalafil has a quicker onset of action and a longer duration of action - around 36 hours - hence the need to be aware of the potential for adverse drug interactions for nearly 2 days after the intake of a single tablet. 

For other small molecules, the mechaiusm of action is still unclear. For example, sildenafil and structural analogs have recently been shown to correct trafficking of deltaF508 CFTR mutants (19, 21). Sildenafil is an inhibitor of phosphodiesterase activity however, the link between this function and CFTR trafficking correction remains to be elucidated. 

Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, Liao J, Luo Y, Zhang D, Thomas DY, Hanrahan JW. Structural analogue of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defecf. Mol. Pharmacol. 2007. 

Fig. 7. Comparison of the chemical structures of (a) sildenafil (5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonyl-phenyl]-1-methyl-3-propyl-4H-pyrazolo[5,4-e]pyrimidin-7-one) and (b) vardenafil (2-[2-ethoxy-5-(4-ethylpiperazin-1-yl) sulfonylphenyl]-5-methyl-7-propyl-1 H-imidazo[5,1 -f][1,2,4]triazin-4-one) illustrates that these retain the bicyclic guanine core, but differ in the arrangement of nitrogen atoms. Comparison of the cocrystal structures of PDE5 in complex with sildenafil (PDB ID 2H42) and vardenafil (PDB ID 1UHO) shows that the binding mode of both sildenafil and vardenafil is similar to the binding mode of the guanine ring in the 5 -GMP complex. The interaction with the conserved Gln817 is shown.

Wang H, Ye M, Robinson H et al (2008) Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Mol Pharmacol 73 104-110... 

Bell, A.S., Brown, A.S., and Terrett, N.K. European Patent, EP 0463 756,1991. Terrett, N.K. et al.. Sildenafil (Viagra ), a potent and selective inhibitor of type-5 cGMP phosphodiesterase with high utihty for the treatment of male erectile dysfunction, Bioorg. Med. Client. Lett., 6, 1819, 1996. Elguero, J. et al.. Packing modes in eight 3-ethoxycarbonylpyrazole derivatives. Influence on the crystal structure and annular tautomerism. Heterocycles, 50, 227, 1999. 

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