ABSTRACT
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.
Subject(s)
Imidazoles/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Thiazoles/chemistry , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Disease Models, Animal , Dizocilpine Maleate/toxicity , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Female , Half-Life , Molecular Docking Simulation , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Psychotic Disorders/drug therapy , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/therapeutic useABSTRACT
The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Parkinson Disease/drug therapy , Pyridones/pharmacology , Animals , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Dose-Response Relationship, Drug , Drug Stability , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Imidazoles/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Parkinson Disease/enzymology , Parkinson Disease/metabolism , Pyridones/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed.
