Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.

Autor:	Li P; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Zheng H; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Zhao J; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Zhang L; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Yao W; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Zhu H; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Beard JD; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Ida K; Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan., Lane W; Department of Structural Biology, Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States., Snell G; Department of Structural Biology, Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States., Sogabe S; Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan., Heyser CJ; Department of Neurosciences, University of California, San Diego , 9500 Gilman Drive, #0608, La Jolla, California 92093, United States., Snyder GL; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Hendrick JP; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Vanover KE; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Davis RE; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States., Wennogle LP; Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Feb 11; Vol. 59 (3), pp. 1149-64. Date of Electronic Publication: 2016 Feb 02.
DOI:	10.1021/acs.jmedchem.5b01751
Abstrakt:	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.
Databáze:	MEDLINE
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