Skip to main content
SpringerLink
Log in

Quinoxaline-2,3-diones: potential d-amino acid oxidase (DAAO) inhibitors

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A family of quinoxaline-2,3-diones was prepared and evaluated to exhibit d-amino acid oxidase (DAAO) inhibitory activities with IC50 values ranging from 0.6 to 15 μM in vitro. SAR analysis revealed their binding modes with DAAO and provided an important clue for further design of highly potent DAAO inhibitors with novel structures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Scheme 3
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adage T, Trillat AC, Quattropani A, Perrin D, Cavarec L, Shaw J, Guerassimenko O, Giachetti C, Greco B, Chumakov I, Halazy S, Roach A, Zaratin P (2008) In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol 18:200–214

    Article  CAS  PubMed  Google Scholar 

  • Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A (1998) Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biol Psychiatry 43:811–816

    Article  CAS  PubMed  Google Scholar 

  • Bartlett GR (1948) The inhibition of d-amino acid oxidase by benzoic acid and various monosubstituted benzoic acid derivatives. JACS 70:1010–1011

    Article  CAS  Google Scholar 

  • Berry JF, Ferraris DV, Duvall B, Hin N, Rais R, Alt J, Thomas AG, Rojas C, Hashimoto K, Slusher BS, Tsukamoto T (2012) Synthesis and SAR of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones as inhibitors of d-amino acid oxidase. ACS Med Chem Lett 3:839–843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Buckle DR, Foster KA, Taylor JF, Tedder JM, Thody VE, Webster RA, Bermudez J, Markwell RE, Smith SA (1987) Novel 1H-benzimidazol-4-ols with potent 5-lipoxygenase inhibitory activity. J Med Chem 30:2216–2221

    Article  CAS  PubMed  Google Scholar 

  • Chen XL, Li XY, Qian SB, Wang YC, Zhang PZ, Zhou XJ, Wang YX (2012) Down-regulation of spinal d-amino acid oxidase expression blocks formalin-induced tonic pain. Biochem Biophys Res Commun 421:501–507

    Article  CAS  PubMed  Google Scholar 

  • D’Aniello A, D’Onofrio G, Pischetola M, D’Aniello G, Vetere A, Petrucelli L, Fisher GH (1993) Biological role of d-amino acid oxidase and d-aspartate oxidase, effects of d-amino acids. J Biol Chem 268:26941–26949

    PubMed  Google Scholar 

  • Duplantier AJ, Becker SL, Bohanon MJ, Borzilleri KA, Chrunyk BA, Downs JT, Hu LY, El-Kattan A, James LC, Liu SP, Lu JM, Maklad N, Mansour MN, Mente S, Piotrowski MA, Sakya SM, Sheehan S, Steyn SJ, Strick CA, Williams VA, Zhang L (2009) Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent d-amino acid oxidase (DAAO) inhibitors. J Med Chem 52:3576–3585

    Article  CAS  PubMed  Google Scholar 

  • Ferraris DV, Tsukamoto T (2011) Recent advances in the discovery of d-amino acid oxidase inhibitors and their therapeutic utility in schizophrenia. Curr Pharm Des 17:103–111

    Article  CAS  PubMed  Google Scholar 

  • Ferraris D, Duvall B, Ko YS, Thomas AG, Rojas C, Majer P, Hashimoto K, Tsukamoto T (2008) Synthesis and biological evaluation of d-amino acid oxidase inhibitors. J Med Chem 51:3357–3359

    Article  CAS  PubMed  Google Scholar 

  • Gong N, Gao ZY, Wang YC, Li XY, Huang JL, Hashimoto K, Wang YX (2011) A series of d-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats. J Pharmacol Exp Ther 336:282–293

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, Tsukamoto T (2009) Co-administration of a d-amino acid oxidase inhibitor potentiates the efficacy of d-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry 65:1103–1106

    Article  CAS  PubMed  Google Scholar 

  • Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, Catinari S, Ermilov M (2005) d-Serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatmentrefractory schizophrenia. Biol Psychiatry 57:577–585

    Article  CAS  PubMed  Google Scholar 

  • Hisashi M, Ikuko M, Ken H, Yasuzo N, Kiyoshi S, Chiaki S, Retsu M (1996) Three-dimensional structure of porcine kidney d-amino acid oxidase at 3.0 A resolution. J Biochem (Tokyo) 120:14–17

    Article  Google Scholar 

  • Hondo T, Warizaya M, Niimi T, Namatame I, Yamaguchi T, Nakanishi K, Hamajima T, Harada K, Sakashita H, Matsumoto Y, Orita M, Takeuchi M (2013) 4-hydroxypyridazin-3(2H)-one derivatives as novel d-amino acid oxidase inhibitors. J Med Chem 56:3582–3592

    Article  CAS  PubMed  Google Scholar 

  • Hopkins SC, Zhao FY, Bowen CA, Fang X, Wei HF, Heffernan ML, Spear KL, Spanswick DC, Varney MA, Large TH (2013a) Pharmacodynamic effects of a d-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic pain. J Pharmacol Exp Ther 345:502–511

    Article  CAS  PubMed  Google Scholar 

  • Hopkins SC, Heffernan ML, Saraswat LD, Bowen CA, Melnick L, Hardy LW, Orsini MA, Allen MS, Koch P, Spear KL, Foglesong RJ, Soukri M, Chytil M, Fang QK, Jones SW, Varney MA, Panatier A, Oliet SHR, Pollegioni L, Piubelli L, Molla G, Nardini M, Large TH (2013b) Structural, kinetic, and pharmacodynamic mechanisms of d-amino acid oxidase inhibition by small molecules. J Med Chem 56:3710–3724

    Article  CAS  PubMed  Google Scholar 

  • Huang JL, Chen XL, Guo C, Wang YX (2012) Contributions of spinal d-amino acid oxidase to bone cancer pain. Amino Acids 43:1905–1918

    Article  CAS  PubMed  Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    Article  CAS  PubMed  Google Scholar 

  • Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF, D’Souza C, Saksa J, Woods SW, Javitt DC (2010) High dose d-serine in the treatment of schizophrenia. Schizophr Res 121:125–130

    Article  PubMed Central  PubMed  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Arch Gen Psychiatry 51:199–214

    Article  CAS  PubMed  Google Scholar 

  • Lu JM, Gong N, Wang YC, Wang YX (2012) d-Amino acid oxidase-mediated increase in spinal hydrogen peroxide is mainly responsible for formalin-induced tonic pain. Br J Pharmacol 165:1941–1955

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Medaer B, Aken KV, Hoornaert G (1994) Synthesis of new [1,2,3]triazoles and 1H-tetrazoles via reactions of 3, (5)-(DI)chloro-2H-1,4-(benz)oxazin-2-ones with Diazo-compounds or sodium-Azide. Tetrahedron Lett 35:9767–9770

    Article  CAS  Google Scholar 

  • Millan MJ (2005) N-methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179:30–53

    Article  CAS  PubMed  Google Scholar 

  • Orozco-Ibarra M, Medina-Campos ON, Sanchez-Gonzalez DJ, Martinez-Martinez CM, Floriano-Sanchez E, Santamaria A, Ramirez V, Bobadilla NA, Pedraza-Chaverri J (2007) Evaluation of oxidative stress in d-serine induced nephrotoxicity. Toxicology 229:123–135

    Article  CAS  PubMed  Google Scholar 

  • Raje M, Hin N, Duvall B, Ferraris DV, Berry JF, Thomas AG, Alt J, Rojas C, Slusher BS, Tsukamoto T (2013) Synthesis of kojic acid derivatives as secondary binding site probes of d-amino acid oxidase. Bioorg Med Chem Lett 23:3910–3913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sethuraman R, Lee TL, Tachibana S (2009) d-serine regulation: a possible therapeutic approach for central nervous diseases and chronic pain. Mini-Rev Med Chem 9:813–819

    Article  CAS  PubMed  Google Scholar 

  • Smith SM, Uslaner JM, Hutson PH (2010) The therapeutic potential of d-amino acid oxidase (DAAO) inhibitors. Open Med Chem J 4:3–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sparey T, Abeywickrema P, Almond S, Brandon N, Byrne N, Campbell A, Hutson PH, Jacobson M, Jones B, Munshi S, Pascarella D, Pike A, Prasad GS, Sachs N, Sakatis M, Sardana V, Venkatraman S, Young MB (2008) The discovery of fused pyrrole carboxylic acids as novel, potent d-amino acid oxidase (DAO) inhibitors. Bioorg Med Chem Lett 18:3386–3391

    Article  CAS  PubMed  Google Scholar 

  • Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167:127–135

    Article  CAS  PubMed  Google Scholar 

  • Tsai G, Yang P, Chung LC, Lange N, Coyle JT (1998) d-Serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44:1081–1089

    Article  CAS  PubMed  Google Scholar 

  • Yang CR, Svensson KA (2008) Allosteric modulation of NMDA receptor via elevation of brain glycine and d-serine: the therapeutic potentials for schizophrenia. Pharmacol Ther 120:317–332

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially supported by the National Natural Science Foundation, China (No: 81202397); the Shanghai Natural Science Foundation Project, Shanghai, China (No: 12ZR1415400) and the Instrumental Analysis Center of Shanghai Jiao Tong University.

Author information

Authors and Affiliations

  1. School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai, 200240, China

    Dongsheng Xie, Yanchao Wang, Jin Xie, Jun Lu, Junjun Cui, Man Zhang, Lei Fu & Yongxiang Wang

Authors
  1. Dongsheng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanchao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junjun Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Man Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lei Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yongxiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lei Fu or Yongxiang Wang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, D., Wang, Y., Xie, J. et al. Quinoxaline-2,3-diones: potential d-amino acid oxidase (DAAO) inhibitors. Med Chem Res 23, 4977–4989 (2014). https://doi.org/10.1007/s00044-014-1068-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-014-1068-z

Keywords

Search

Navigation