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Figure 5. Vardenafil-hydrochloride, a clinical candidate for the treat-
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In comparison to the known pyrazolo[4,3-d]pyrimidin-
7-one PDE inhibitors (e.g., Sildenafil)12 and the
dihydropurinones,11,38ꢀ40 the imidazotriazinones show
substantially improved PDE 5 inhibition and improved
selectivity over PDE 1. The piperazine-sulfonamide
residue renders these PDE inhibitors highly soluble and
hydrophilic.
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The N-ethylpiperazino derivative Vardenafil (14, Fig. 5)
shows excellent PDE inhibitory activity and was selec-
ted as a potential candidate for further in vivo studies. It
shows in vivo activity in a conscious rabbit model with a
minimal effective dose of 3 mg/kg (po administration).41
All compounds of the imidazo[5,1-f][1,2,4]triazin-4(3H)-
one type mentioned above are highly cGMP-PDE 5
selective and show IC50 values for PDE 3 and PDE 4
greater than 500 nM.
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Summary
We have shown that with the imidazo[5,1-f][1,2,4]tri-
azin-4(3H)-one heterocyclic system, highly potent inhibi-
tors of cGMP-metabolizing PDE 5 can be obtained with
superior in vitro potency and selectivity to other known
purine-isosteric systems. BAY 38–9456 (Vardenafil-
hydrochloride), a highly potent and selective PDE 5
inhibitor has been submitted to the FDA for approval
for the treatment of erectile dysfunction.
33. Clarke, R.; Garside, S. C.; Lunts, L. H. C.; Hartley, D.;
Hornby, R.; Oxford, A. W. J. Chem. Soc., Perkin Trans. 1
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36. All reported IC50 values refer to human PDE 5 and bovine
PDE 1 except otherwise noted.
References and Notes
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37. Bischoff, E.; Niewoehner, U.; Haning, H.; Es-Sayed, M.;
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