The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia

The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed...

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Veröffentlicht in:	Bioorg. Med. Chem. Lett 2012-04, Vol.22 (7), p.2585-2589
Hauptverfasser:	Ho, Ginny D., Michael Seganish, W., Bercovici, Ana, Tulshian, Deen, Greenlee, William J., Van Rijn, Rachel, Hruza, Alan, Xiao, Li, Rindgen, Diane, Mullins, Deborra, Guzzi, Mario, Zhang, Xiaoping, Bleickardt, Carina, Hodgson, Robert
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Area Under Curve Biological and medical sciences Crystallography, X-Ray Cyclic Nucleotide Phosphodiesterases, Type 3 - chemistry Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism Cyclic Nucleotide Phosphodiesterases, Type 7 - chemistry Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism Dizocilpine Maleate Haplorhini Humans Hyperactivity Hyperkinesis - chemically induced Hyperkinesis - drug therapy Hyperkinesis - enzymology Imidazoles - administration & dosage Imidazoles - chemical synthesis Imidazoles - pharmacokinetics Isoquinolines - administration & dosage Isoquinolines - chemical synthesis Isoquinolines - pharmacokinetics Male Medical sciences Mental disorders Models, Molecular PDE10A Pharmacology. Drug treatments Phosphodieasterase inhibitors phosphodiesterase Phosphodiesterase Inhibitors - administration & dosage Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - pharmacokinetics Phosphoric Diester Hydrolases - chemistry Phosphoric Diester Hydrolases - metabolism Psychotropic Drugs - administration & dosage Psychotropic Drugs - chemical synthesis Psychotropic Drugs - pharmacokinetics Rats Schizophrenia Schizophrenia - drug therapy Schizophrenia - enzymology Structure-Activity Relationship
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Zusammenfassung:	The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.01.113