title: Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.
abstract: A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Beard
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Ida
authors.affiliation: Department of Structural Biology, Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Weston
authors.initials: W
authors.lastname: Lane
authors.affiliation: Department of Structural Biology, Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Snell
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.affiliation: Department of Neurosciences, University of California, San Diego , 9500 Gilman Drive, #0608, La Jolla, California 92093, United States.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Heyser
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hendrick
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Wennogle
mesh_terms: D000818:Animals; D002417:Cattle; D003072:Cognition Disorders / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1