Substrate-analogous PDE5 Inhibitors

A next step towards more potent inhibitors is exemplified by DMPPO (9), featuring a more hydrophobic right-hand portion of the core and the addition of a polar sulfonamide to the aromatic ring. These pyrazolopyrimidinones have been used for the construction of PDE inhibitors since the mid 1980s [17]. DMPPO in particular 

The key glutamine residue is engaged in a bidentate interaction, which is also postulated for the recognition cGMP itself. 

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Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors. Bioorg. Med. Chem. Lett. 15, 3900-7. 

Figure 9.11 Indole-type PDE5 inhibitors. In contrast to the substrate-analogous inhibitors, the key glutamine residue is engaged in only a single - not a bidentate - H bond to the indole NH of tadalafil (see inset).

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