Synthesis and biological evaluation of D-amino acid oxidase inhibitors.
D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including d-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[ d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chloro-benzo[ d]isoxazol-3-ol (CBIO) potently inhibited DAAO with an IC50 in the submicromolar range. Oral administration of CBIO in conjunction with d-serine enhanced the plasma and brain levels of d-serine in rats compared to the oral administration of d-serine alone.
MGI Pharma, Inc.
Dana
D
Ferraris
Bridget
B
Duvall
Yao-Sen
YS
Ko
Ajit G
AG
Thomas
Camilo
C
Rojas
Pavel
P
Majer
Kenji
K
Hashimoto
Takashi
T
Tsukamoto
D000284:Administration, Oral; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
C531067:5-chlorobenzo(d)isoxazol-3-ol; D001583:Benzoxazoles; D007555:Isoxazoles; D012694:Serine; D003605:D-Amino-Acid Oxidase