Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition.
A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1.
Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: wataru.hamaguchi@astellas.com.
Wataru
W
Hamaguchi
Naoyuki
N
Masuda
Mai
M
Isomura
Satoshi
S
Miyamoto
Shigetoshi
S
Kikuchi
Yasushi
Y
Amano
Kazuya
K
Honbou
Takuma
T
Mihara
Toshihiro
T
Watanabe
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; 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; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; C031000:benzimidazole; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
Benzimidazole; CYP1A2; PDE10A inhibitor; Schizophrenia