4-Hydroxypyridazin-3(2<i>H</i>)-one Derivatives as Novel <scp>d</scp>-Amino Acid Oxidase Inhibitors

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

doi:10.1021/jm400095b

Cited by 39 publications

(46 citation statements)

References 40 publications

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“…PDB code: ¼ 3W4I, 3W4J and 3W4K, are found in the tetramer form. [18] Moreover, the porcine DAAO also shows an oligomerisation state in the solution which depends on the protein concentration. [16] One of the main objectives of this work is to study the influence of chain B and chain B -D to the interaction between h-DAAO and the inhibitor in chain A.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Wichapong

Nueangaudom

Pianwanit

et al. 2014

Molecular Simulation

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Schizophrenia is a mental illness; most affected people live in developing countries, and neither appropriate treatment nor commercial drugs are currently available. One possibility is to inhibit human-D-amino acid oxidase (h-DAAO). In this study, molecular dynamic simulations of the monomer, dimer and tetramer forms of h-DAAO complexed with the inhibitor 3-hydroxyquinolin-2(1H)-one(2) were performed. Seven residues, Leu51, Gln53, Leu215, Tyr228, Ile230, Arg283 and Gly313, were identified as essential for interacting with the inhibitor. Molecular docking of h-DAAO with pyrrole, quinoline and kojic acid derivatives, representing 69 known or potential h-DAAO inhibitors, was also performed. The results indicated that the activity of the inhibitor can be improved by modifying the compounds to have a substituent group capable of interacting with the side chain of Tyr228. Van der Waals interactions of the inhibitor with the hydrophobic pocket of h-DAAO and electrostatic interactions or H-bonds with Arg283 and Gly313 were important elements in determining the efficiency of the inhibitor. These results provide information on the interaction between h-DAAO and its inhibitors at the molecular level and can aid in the design of novel inhibitors against h-DAAO for new drug development in the treatment of schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Wichapong

Nueangaudom

Pianwanit

et al. 2014

Molecular Simulation

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“…[31][32][33][34][35] Of these structures, the complex of imino-3,4-dihydroxyphenylalanine (DOPA) bound to hDAO provides the best option for the design of an anchor molecule for using in situ click chemistry screening. Specifically, our aim was to generate azide-or alkyne-bearing derivatives of the imino-DOPA ligand molecule.…”

Section: Resultsmentioning

confidence: 99%

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

Toguchi

Hirose

Yorita

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry.Key words fragment-based lead discovery; templated reaction; ligand-binding site; drug discovery; triazole formation; ligand affinity Although D-amino acids exist in a wide range of organisms, they are nonetheless often called unnatural amino acids. D-Serine is abundant in the forebrain and acts as an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors to enhance neurotransmission. 1) D-Amino acid oxidase (DAO) was the first flavoenzyme to be identified, in 1935 by Krebs,2) and catalyzes the oxidative deamination reaction of D-amino acids. This reaction by human DAO (hDAO) in the brain primarily converts D-serine to hydroxypyruvate to regulate the concentration of D-serine. The overexpression of hDAO in the brain therefore causes neuropsychiatric disorders such as schizophrenia, a serious public health problem that affects nearly 0.8% of the global population, by reducing the amount of D-serine below the level required for adequate neuronal function.3,4) Furthermore, a protein from the human gene G72 has been identified as an interacting partner to activate hDAO, and the association of both DAO and gene G72 with schizophrenia together with activation of hDAO activity by a G72 protein product points to the involvement of the regulation of NMDA receptor. 5) Thus, hDAO inhibitors have potential to be lead compounds to the development of therapeutic agents for schizophrenia.Within the realm of click chemistry research, triazole formation between organic azide and alkyne is widely recognized. Triazole formation includes the 1,3-dipolar reaction known as the Huisgen cycloaddition, [6][7][8][9] and catalytic reactions that selectively afford the corresponding 1,4-substituted triazole or 1,5-substituted triazole using monovalent copper 10,11) or ruthenium reagents, 12,13) respectively. In situ click chemistry is a target-guided synthesis (TGS) method for the fast and efficient production of potential inhibitors against target biomolecules such as enzymes. Using this approach, complementary alkyne and azide building are assembled at binding sites and then accelerate the Huisgen 1,3-dipolar cycloaddition reaction to afford the corresponding conventional triazole, as illustrated in Fig. 1.To date, in situ click chemistry research has garnered success in inhibitor explorations where acetylcholinester-

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“…5 Similarly, a group at Astellas reported potent DAAO inhibitors including 2a–b based on a 4-hydroxypyridazin-3(2 H )-one scaffold with a phenethyl group extending to the secondary binding site. 6 2-Substituted 6-hydroxy-1,2,4-triazine-3,5(2 H ,4 H )-diones such as 3 exhibited not only potent DAAO inhibitory activity but also improved metabolic stability compared to 1–2 in liver microsomes. 7 This secondary binding site was also exploited by carboxylate-based DAAO inhibitors such as 4 8 and 5 .…”

mentioning

confidence: 99%

“…In general, the SAR trends are similar to those of 4-hydroxypyridazin-3(2 H )-one and 6-hydroxy-1,2,4-triazine-3,5(2 H ,4 H )-dione derivatives. 6, 7 Two-unit chains, -CH 2 CH 2 - and -CH 2 S- appear to be very effective linkers connecting the aryl group and the 5-hydroxy-1,2,4-triazin-6(1 H )-one moiety, providing some of the most potent DAAO inhibitors within the series.…”

mentioning

confidence: 99%

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d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Hin

Duvall

Berry

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized as a new class of D-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives showed potent inhibitory activity against human DAAO with IC50 values in the nanomolar range. Among them, 6-hydroxy-3-phenethyl-1,2,4-triazin-5(2H)-one 6b and 3-((6-fluoronaphthalen-2-yl)methylthio)-6-hydroxy-1,2,4-triazin-5(2H)-one 6m were found to be metabolically stable in mouse liver microsomes. In addition, compound 6b was found to be orally available in mice and able to enhance plasma D-serine levels following its co-administration with D-serine compared to the oral administration of D-serine alone.

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4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors

Cited by 39 publications

References 40 publications

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

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