Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.

Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.
Bioorg Med Chem. 2019 Jul 06;:
Authors: Chino A, Honda S, Morita M, Yonezawa K, Hamaguchi W, Amano Y, Moriguchi H, Yamazaki M, Aota M, Tomishima M, Masuda N
Abstract
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.
PMID: 31301949 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry - July 5, 2019 Category: Chemistry Authors: Chino A, Honda S, Morita M, Yonezawa K, Hamaguchi W, Amano Y, Moriguchi H, Yamazaki M, Aota M, Tomishima M, Masuda N Tags: Bioorg Med Chem Source Type: research