Chapter Four - Selective Inhibitors of PDE2, PDE9, and PDE10: Modulators of Activity of the Central Nervous System

Abstract Although superficially similar, the currently most advanced inhibitors of PDE2, PDE9, and PDE10 for central nervous system disorders differ in a number of ways. PDE9 appears to be very restrictive in its binding motif requirements: in essence only one chemotype, emulating the GMP bidentate-binding motif, covers the known PDE9 chemical space. A much larger diversity of compounds is described for inhibitors of PDE2: it appears as if the less stringent requirements for binding to the invariant glutamine (Gln) in combination with the induced hydrophobic (selectivity) pocket allow a much broader variety of inhibitor chemotypes. PDE10 also has less stringent structural requirements and accepts more structurally diverse inhibitors compared to PDE9. The PDE10-unique Q2 pocket provides an additional opportunity for diversity in compounds targeting this enzyme. In special cases, high affinities can be obtained without even interacting with the central Gln.