The Discovery of the Longacting PDE5 Inhibitor PF-489791 for the Treatment of Pulmonary Hypertension - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 176

hand, displayed outstanding PDE5 potency and selectivity. However, the
altered physicochemistry was sucient to compromise permeability, as evi-
denced by a Caco-2 permeability assay. These findings were consistent with
Lipinski rules. 27 In particular, the two additional heteroatoms from the amide
motif raised both the H-bond donor/acceptor count (HBD/HBA) and the
topological polar surface area (TPSA), potentially key influencing properties
relative to permeability.
The PDE5 selectivity of the amide 5 can be rationalised from the co-crystal
structure (Figure 8.8). Selectivity over PDE6 through the C3 amide substituent
is thought to be driven primarily by the interactions with the residues
Met816Leu(PDE6) and especially Leu804Met(PDE6) at the ''alkoxy'' pocket
entrance. Selectivity over PDE10 can be rationalised via the extended N1
substituent interacting with the Ala783Tyr(PDE10) residue change, where the
tyrosine in PDE10 occludes the ''alkoxy'' pocket. The C3 amide substituent has
also influenced selectivity over PDE11, where residues equivalent to positions
804 and 816 are Ile and Leu, respectively. These key features of the catalytic
domain binding mode of 5 were factored in as we sought to address the poor
absorption.
Figure 8.8 Co-crystal structure of amide derivative 5 with the catalytic domain of
PDE5 and the solid rendering to PDE5 binding site surface coloured by
hydrophobicity. The GLN817 bidentate H-bond is illustrated together
with the LEU804 ''isopropyl'' motif believed to play a role in PDE
selectivity, visible behind the C3 amide group.