title: 4-Hydroxypyridazin-3(2H)-one derivatives as novel D-amino acid oxidase inhibitors.
abstract: D-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. takeshi.hondo@astellas.com
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hondo
authors.forename: Masaichi
authors.initials: M
authors.lastname: Warizaya
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Ichiji
authors.initials: I
authors.lastname: Namatame
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Keita
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hamajima
authors.forename: Katsuya
authors.initials: K
authors.lastname: Harada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakashita
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010539:Permeability; D011487:Protein Conformation; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; C062482:pyridazine; D016291:Dizocilpine Maleate; D003605:D-Amino-Acid Oxidase