Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.
In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition.
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ayaka.chino@astellas.com.
Ayaka
A
Chino
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Naoyuki
N
Masuda
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Yasushi
Y
Amano
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Kazuya
K
Honbou
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Takuma
T
Mihara
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Mayako
M
Yamazaki
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Masaki
M
Tomishima
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; C031000:benzimidazole; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
Benzimidazole; Imidazopyridine; Metabolic stability; PDE10A inhibitor; Schizophrenia