Discovery of selective biaryl ethers as PDE10A inhibitors: Improvement in potency and mitigation of Pgp-mediated efflux

Fragment‐ and negative image‐based screening of phosphodiesterase 10A inhibitors

“…In total, four hybrid models (I–IV; Figure ; Figure S4) were generated utilizing the ligand‐binding pockets of two human PDE10A X‐ray crystal structures (PDB: 4HEU; 3SN7; Malamas et al., ; Rzasa et al., ). Before building the cavity‐based negative images or NIB (negative image‐based) models with PANTHER (Niinivehmas et al., ), protons were added to the protein structures using REDUCE 3.24.130724 (Word, Lovell, Richardson, & Richardson, ).…”

“…Note that the direct H‐bond between Tyr514 and 2 could also be substituted by a water bridge (not shown). Those residues that were notably adjusted by the MM / GBSA routine are shown with both the original (transparent sticks; PDB : 3 SN 7 in A, C and 4 HEU in d, f, g, and i) (Malamas et al., ; Rzasa et al., ) and optimized poses; otherwise, only original side chain conformations are shown (panel I) [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…For the first model (Figure d, e), PDB‐entry 4HEU (Rzasa et al., ) was used as the input template structure in building the cavity's negative image. For PANTHER (Niinivehmas et al., ), box radius was set to 12 Å and the model dimensions were kept close to the protein‐bound biaryl ether inhibitor (residue name: 15J ) with ligand distance limit of 1.0 Å.…”

“…(a) The 3D structure of the PDE 10A (cyan cartoon; PDB : 2 OUN ; chain A; Wang et al., ) shown with adenosine monophosphate ( AMP ; pink CPK model). (b) The AMP (ball‐and‐stick model with pink backbone) binding is shown with the key residues (stick models with white backbone) such as Gln716 and His515 forming H‐bonds (magenta dotted lines; PDB : 4 HEU ; A chain; Rzasa et al., ) and participating with the divalent ions in the hydrolysis of cyclic AMP (or cAMP ) or cyclic GMP ( cGMP ; nucleoside 3′,5′‐cyclic phosphate + H 2 O = nucleoside 5′‐phosphate). (c) The binding of inhibitors such as the biaryl ether 15J (ball‐and‐stick model with magenta backbone) does not involve the divalent ions.…”

Synthesis and <i>in Vivo</i> Evaluation of Novel Quinoline Derivatives as Phosphodiesterase 10A Inhibitors

“…[10][11][12][13][14] PDE10A inhibitors have therefore garnered attention as a new therapeutic approach for the treatment of schizophrenia. [15][16][17][18][19][20][21][22][23][24][25] Among reported PDE10A inhibitors, TP-10 and MP-10 ( Fig. 1) have extremely potent PDE10A inhibitory activity and high selectivity against other PDEs, and both of these compounds have been reported to be active in the mouse behavioral model for positive symptoms.…”