Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives

“… General structure of novel compounds 3 – 23 , designed based on potent phosphodiesterase 10A (PDE10) inhibitors and active serotonin receptor ligands [ 20 , 25 , 26 , 28 , 29 , 30 ]. The phthalimide cores and amine groups are highlighted in blue and green, respectively.…”

“…Previously, these amines were used in the design of potent 5-HT 1A and 5-HT 7 ligands (compound 18 and PZ-376, Figure 2 ) [ 26 , 27 , 28 ], and they are partially saturated analogs of isoquinoline, which is present in the structure of papaverine, a potent PDE10A inhibitor. Moreover, the benzimidazole moiety can be found in the structure of numerous PDE inhibitors and serotonin ligands (compound 10 , Figure 2 ) [ 29 , 30 ]. Finally, a phenyl ring was chosen instead of a heterocyclic amine group in order to examine the effect of amine substitution on selected 5-HTRs affinity and PDE10A inhibitory activity.…”

Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors

“…Benzimidazole is a core structural moiety found in some of the important drugs like albendazole ( I ), mebendazole ( II ), thiabendazole ( III ), rabeprazole ( IV ), and so forth. Literature survey revealed that coumarin ( V ) scaffolds were proved to increase the cAMP levels through the specific inhibition of PDE3 in accordance with their common structural features [ 10 ] and pyrazole ( VI ) derivatives have been explored for the identification of phosphodiesterase (PDE4) inhibitors as is exemplified by the discovery and development of tofimilast [ 11 ]; also most of the benzimidazole ( VII ) derivatives have shown very prominent PDE (10A) activity [ 12 ]. Coumarin, pyrazole, and benzimidazole core structural moiety are found in some of the important PDE inhibition compounds by Yang et al [ 13 ] ( Figure 1 ).…”

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

“…The active site is well characterized from X-ray crystallography as being small (<300 Å 2 ) and relatively polar [12,13]. A large number of PDE10 inhibitors have been reported (including Papaverine) [14][15][16][17][18][19][20][21], and currently more than 180 patent applications have been published [22]. Many of these are in various stages of clinical trials, but none of these inhibitors have yet reached the market [7,23].…”