Discovery of benzo[d]imidazo[5,1-b]thiazole as a new class of phosphodiesterase 10A inhibitors.
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.
Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra 400709, India.
Abhisek
A
Banerjee
Lakshminarayana
L
Narayana
Firoj A
FA
Raje
Dnyandeo V
DV
Pisal
Pradip A
PA
Kadam
Srinivas
S
Gullapalli
Hemant
H
Kumar
Sandeep V
SV
More
Malini
M
Bajpai
Ramachandra Rao
RR
Sangana
Satyawan
S
Jadhav
Girish S
GS
Gudi
Neelima
N
Khairatkar-Joshi
Ravi R T
RR
Merugu
Sreedhara R
SR
Voleti
Laxmikant A
LA
Gharat
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006207:Half-Life; D007093:Imidazoles / Q000737:chemistry*; D062105:Molecular Docking Simulation; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011618:Psychotic Disorders / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
D014150:Antipsychotic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D013844:Thiazoles; D016291:Dizocilpine Maleate; C029899:imidazole; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases
Anti-psychotics; Conditioned Avoidance Response; MK-801; Phosphodiesterase 10A inhibitors; Schizophrenia