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

Ayaka Chino; Shugo Honda; Masataka Morita; Koichi Yonezawa; Wataru Hamaguchi; Yasushi Amano; Hiroyuki Moriguchi; Mayako Yamazaki; Masaki Aota; Masaki Tomishima; Naoyuki Masuda

doi:10.1016/j.bmc.2019.07.010

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 Aug 15;27(16):3692-3706. doi: 10.1016/j.bmc.2019.07.010. Epub 2019 Jul 6.

Affiliations

¹ Functional Molecules, Modality Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ayaka.chino@astellas.com.
² Functional Molecules, Modality Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

PMID: 31301949
DOI: 10.1016/j.bmc.2019.07.010

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.

Keywords: Brain penetration; P-gp liability; PDE10A inhibitor; Schizophrenia; Y-maze.

MeSH terms

Drug Design
Humans
Molecular Structure
Phosphodiesterase Inhibitors / pharmacology
Phosphodiesterase Inhibitors / therapeutic use*
Structure-Activity Relationship

Substances

Phosphodiesterase Inhibitors