Design, synthesis and structure-activity relationship of novel tricyclic benzimidazolone derivatives as potent 18 kDa translocator protein (TSPO) ligands.
The 18 kDa translocator protein (TSPO) was identified as a discrete receptor for diazepam (1). Since TSPO in the central nervous system (CNS) is believed to regulate neurosteroids biosynthesis, selective TSPO ligands are expected to be useful in the treatment of psychiatric disorders. We synthesized three novel tricyclic benzimidazolone derivatives, and selected the dihydroimidazoquinolinone derivative 27 as a lead TSPO ligand. Study of the structure-activity relationship (SAR) of dihydroimidazoquinolinone derivatives revealed compounds with potent affinity for TSPO (subnanomolar K(i) values), but poor metabolic stability. The optimization of these compounds led to compound 48 with potent affinity for TSPO and good in vitro PK profile.
Dainippon Sumitomo Pharma Co. Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan. takayuki-fukaya@ds-pharma.co.jp
Takayuki
T
Fukaya
Toru
T
Kodo
Takeo
T
Ishiyama
Hiroyuki
H
Nishikawa
Satoko
S
Baba
Shuji
S
Masumoto
D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006207:Half-Life; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D051379:Mice; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000083:Acetanilides; D001562:Benzimidazoles; D002352:Carrier Proteins; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; C582997:N-methyl-2-(2-oxo-8-(pyridin-3-ylamino)-5,6-dihydro-4H-imidazo(4,5,1-ij)quinolin-1(2H)-yl)-N-phenylacetamide; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C014353:benzimidazolone