Journal of medicinal and pharmaceutical chemistry 2013-05-09

4-Hydroxypyridazin-3(2H)-one derivatives as novel D-amino acid oxidase inhibitors.

Takeshi Hondo, Masaichi Warizaya, Tatsuya Niimi, Ichiji Namatame, Tomohiko Yamaguchi, Keita Nakanishi, Toshihiro Hamajima, Katsuya Harada, Hitoshi Sakashita, Yuzo Matsumoto, Masaya Orita, Makoto Takeuchi

文献索引：J. Med. Chem. 56(9) , 3582-92, (2013)

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摘要

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.