The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Advances in targeting cyclic nucleotide phosphodiesterases

“…2c,d) (see also Supplementary information S1 (figure), part A; Supplementary information S2 (figure)) suggest that two conserved residues, the invariant glutamine and a highly conserved phenylalanine (Phe372 in PDE4D2; Trp621 in PDE11A2), are essential for inhibitor binding 15,16,36,40 . The formation of hydrogen bonds with the invariant glutamine determines the orientation of inhibitors, and conserved hydrophobic residues (Ile336 and Phe340 in PDE4D2) 16,40 form a ‘hydrophobic clamp’ that anchors inhibitors in the pocket and wedges their ring structures against Phe372 in PDE4D2 (Supplementary information S1 (figure), part A) 16,36,38,40 and against Phe456 and Phe729 in PDE9A and PDE10A, respectively (Supplementary information S2 (figure)) 16,17,41–45 .…”

“…More potent and selective inhibitors are then generated by an iterative process of co-crystallography, whereby compounds are identified by additional focused library screening and/or they are chemically synthesized after structure-informed virtual screening and computational design. This approach has resulted in the discovery of several novel pyrazole derivatives as potent and selective PDE4 inhibitors 40,163 , of pyrazolopyrimidinones (such as PF-04447943) as PDE9A inhibitors for cognitive disorders 43,44 , and of pyridopyrazo-loquinolines (such as PF-2545920) as PDE10A inhibitors for the treatment of schizophrenia 41,42,45 . In the latter case, the co-crystallization of lead scaffold triarylimidazole compounds (identified by high-throughput screening of the Pfizer compound library) with the catalytic fragment of PDE10A identified a unique, PDE10A-specific, hydrophobic selectivity pocket for PDE10A inhibitors.…”

A comparative study of binding affinities for 6,7-dimethoxy-4-pyrrolidylquinazolines as phosphodiesterase 10A inhibitors using the linear interaction energy method

“…AD provides a first structural alert on the dataset and is primarily used to check whether a new molecular entity is within the chemical space of the training set or not. For the AD experiment a set of 160 PDE10 inhibitors was retrieved from ChEMBL database [48] and this dataset consist of 6 different scaffolds [19,[49][50][51][52][53] which share no structural similarity with the training set that we used for the binding affinity model development [40]. The G obs values span an energy difference of 3.16 kcal/mol (Fig.…”

Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

“…The SAR development of dihydroimidazoisoquinoline derivatives as PDE10A inhibitors for the treatment of schizophrenia has been the subject of a recent publication [34].…”