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

Ginny D Ho; W Michael Seganish; Ana Bercovici; Deen Tulshian; William J Greenlee; Rachel Van Rijn; Alan Hruza; Li Xiao; Diane Rindgen; Deborra Mullins; Mario Guzzi; Xiaoping Zhang; Carina Bleickardt; Robert Hodgson

doi:10.1016/j.bmcl.2012.01.113

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

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2585-9. doi: 10.1016/j.bmcl.2012.01.113. Epub 2012 Feb 9.

Authors

Ginny D Ho¹, W Michael Seganish, Ana Bercovici, Deen Tulshian, William J Greenlee, Rachel Van Rijn, Alan Hruza, Li Xiao, Diane Rindgen, Deborra Mullins, Mario Guzzi, Xiaoping Zhang, Carina Bleickardt, Robert Hodgson

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. ginny.ho@merck.com

PMID: 22377514
DOI: 10.1016/j.bmcl.2012.01.113

Abstract

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.

MeSH terms

Animals
Area Under Curve
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
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
Models, Molecular
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 / drug therapy
Schizophrenia / enzymology
Structure-Activity Relationship

Substances

Imidazoles
Isoquinolines
Phosphodiesterase Inhibitors
Psychotropic Drugs
Dizocilpine Maleate
PDE10A protein, rat
Phosphoric Diester Hydrolases
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 7
Pde3a protein, rat
Pde7a protein, rat