The discovery of fused pyrrole carboxylic acids as novel, potent d-amino acid oxidase (DAO) inhibitors

Sparey, Tim; Abeywickrema, Pravien; Almond, Sarah; Brandon, Nicholas J.; Byrne, Noel; Campbell, Alister; Hutson, Pete H.; Jacobson, Marlene A.; Jones, Brian V.; Munshi, Sanjeev; Pascarella, Danette; Pike, Andrew; Prasad, G.; Sachs, Nancy A.; Sakatis, Melanie Z.; Sardana, Vinod; Shankar, Viswanathan; Young, Matthew

doi:10.1016/j.bmcl.2008.04.020

Cited by 77 publications

(91 citation statements)

References 11 publications

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“…6(B,C)] although they modulate the short-term cellular D-serine concentration similarly. An increase in the D/(DþL) serine concentration ratio at 24 hours from treatment with both compounds is apparent (a similar result was also observed for plasma D-serine levels of rats treated with the hDAAO inhibitor pyrrole carboxylic acids), 11 which is abolished at 48 hours [ Fig. 6(A)].…”

Section: Discussionsupporting

confidence: 69%

“…A number of recent studies focused on the development of new and effective hDAAO inhibitors as a treatment strategy for schizophrenia by modulating D-serine concentrations in the brain. [10][11][12][13] These studies reported on the synthesis and identification of new hDAAO inhibitors (mainly aromatic compounds that bind in the hDAAO active site, for a structural comparison see Ref. 13) and on their effect on rat brain D-serine concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, and in agreement with the aforementioned model, hDAAO is now considered the target for a new class of drugs (hDAAO inhibitors) to treat schizophrenia. [10][11][12][13] Human DAAO shows the main properties of the dehydrogenase-oxidase class of flavoproteins and shares a low turnover number and a ternary complex (sequential) kinetic mechanism with pig kidney DAAO (pkDAAO, %85% sequence identity). 7 Indeed, this human flavoenzyme can be distinguished from the other known DAAOs because it is a stable homodimer even in the apoprotein form, because the binding of the FAD cofactor is the weakest among the known DAAOs (K d value is in the micromolar range) 1,7 and because it specifically interacts with pLG72 (which is expressed on primates only).…”

Section: Introductionmentioning

confidence: 99%

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Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

et al. 2010

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In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation of the neuromodulator D-serine, an important effector of NMDA-receptor mediated neurotransmission. Experimental evidence supports the concept that D-serine concentration increase by hDAAO inhibition may represent a valuable therapeutic approach to improve the symptoms in schizophrenia patients. This study investigated the effects on hDAAO conformation and stability of the substrate D-serine (or of the pseudo-substrate trifluoro-D-alanine), the FAD cofactor, and two inhibitors (benzoate, a classical substrate-competitive inhibitor and the drug chlorpromazine (CPZ), which competes with the cofactor). We demonstrated that all these compounds do not alter the interaction of hDAAO with its physiological partner pLG72. The ligands used affect the tertiary structure of hDAAO differently: benzoate or trifluoro-D-alanine binding increases the amount of the holoenzyme form in solution and stabilizes the flavoprotein, while CPZ binding favors a protein conformation resembling that of the apoprotein, which is more sensitive to degradation. Interestingly, the apoprotein form of hDAAO binds the substrate D-serine: this interaction increases FAD binding thus increasing the amount of active holoenzyme in solution. Benzoate and CPZ similarly modify the short-term cellular D-serine concentration but affect the cellular concentration of hDAAO differently. In conclusion, the different alteration of hDAAO conformation and stability by the ligands used represents a further parameter to take into consideration during the development of new drugs to cope schizophrenia.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

et al. 2010

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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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“…Efficient synthetic routes to these heterocycles are of great interest (Krutošíková et al 1992;Beccalli et al 2008;Zhao et al 2014) as the furo [3,2-b]pyrrole core has been found in compounds with diverse biological activities (Sparey et al 2008;Fehér et al 2010) or they are used as the fluorescent dyes (Umezawa et al 2008). Heterocyclic compounds containing fiveand six-membered nitrogen heterocyclic rings have also attracted the attention due to the fact that they exhibit many biological interactions (Astakhina et al 2016).…”

Section: Introductionmentioning

confidence: 99%

NMR spectroscopic properties of furo[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazine derivatives

Zemanová¹,

Gašparová²

2017

Nova Biotechnologica Et Chimica

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The discovery of fused pyrrole carboxylic acids as novel, potent d-amino acid oxidase (DAO) inhibitors

Cited by 77 publications

References 11 publications

Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

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

NMR spectroscopic properties of furo[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazine derivatives

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