Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand.
Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of 9b, which showed anxiolytic effect in a rat model. However, 9b, like known benzodiazepines, induced motor impairment. Investigation into the cause of this unexpected side effect and management of 9b off-target binding affinity led to the identification of 10d, which showed oral anxiolytic effect in the rat model with improved safety profile.
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Takayuki
T
Fukaya
Takeo
T
Ishiyama
Satoko
S
Baba
Shuji
S
Masumoto
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001362:Avoidance Learning / Q000187:drug effects; D001583:Benzoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000819:agonists* / Q000737:chemistry; D045744:Cell Line, Tumor; D003220:Conflict, Psychological; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D001583:Benzoxazoles; D002352:Carrier Proteins; D008024:Ligands; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C017057:benzoxazolone