약학회지 (YAKHAK HOEJI)

  • 제56권1호
  • /
  • Pages.42-47
  • /
  • 2012
  • /
  • 0377-9556(pISSN)
  • /
  • 2383-9457(eISSN)
대한약학회 (The Pharmaceutical Society of Korea)
권호 표지

심혈관계 질환 치료제 후보물질 발굴을 위한 Soluble Epoxide Hydrolase 억제평가 방법 개발

Development of Soluble Epoxide Hydrolase Inhibitor Screening Methods for Discovery of Drug Candidate in Cardiovascular Diseases

  • 투고 : 2011.12.16
  • 심사 : 2011.12.21
  • 발행 : 2012.02.29
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Soluble epoxide hydrolase (sEH) is a metabolic regulator of epoxyeicosatrienoic acids (EETs). EETs have many beneficial effects, vasodilation, anti-diabetes, anti-inflammation, cardiovascular protection, renal protection. Therefore, selective sEH inhibitors have a potential for treating these diseases. In the present study, screening methods for sEH inhibitors using PHOME ((3-phenyl-oxiranyl)-acetic acid cyano-(6-methoxynaphthalen-2-yl)-methyl ester) and 14-15-EET as substrates were established. To determine selectivity, microsomal epoxide hydrolase (mEH) inhibition assay was also developed using styrene oxide as a substrate of microsomal epoxide hydrolase. Our results obtained from 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid (AUDA) used as a positive sEH inhibitor and valpromide used as a positive mEH inhibitor showed that these methods are useful for discovery of drug candidates.

키워드

참고문헌

  1. 생명공학정책연구센터 : 주요 질환별 기술개발 동향, 기술동향 2009-5 (2009).
  2. Astrazeneca global : Astrazeneca Annual Report and Form 20- F Information 2006, 16 (2006).
  3. Spiecker, M. and Liao, J. : Cytochrome P450 epoxygenase CYP2J2 and the risk of coronary artery disease. Trends. Cardiovasc. Med. 16, 204 (2006).
  4. Imig, J. D., Carpenter, M. A. and Shaw, S. : The soluble epoxide hydrolase inhibitor AR9281 decreases blood pressure, ameliorates renal injury and improves vascular function in hypertension. Pharmaceuticals 2, 217 (2009).
  5. Mustafa, S., Sharma, V. and McNeill, J. H. : Insulin resistance and endothelial dysfunction: Are epoxyeicosatrienoic acids the link? Exp. Clin. Cardiol. 14, 41 (2009).
  6. Roman, R. J. : P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82, 131 (2001).
  7. Enayetallah, A. E., French, R. A. and Grant, D. F. : Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms. J. Mol. Histol. 37), 133 (2006).
  8. Wolf, N. M., Morisseau, C., Jones, P. D., Hock, B. and Hammock, B. D. : Development of a high-throughput screen for soluble epoxide hydrolase inhibition. Anal. Biochem. 355, 71 (2006).
  9. Parrish, A. R., Chen, G., Burghardt, R. C., Watanabe, T., Morisseau, C. and Hammock, B. D. : Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase. Cell. Biol. Toxicol. 25, 217 (2009).
  10. Xu, D., Li, N., He, Y., Timofeyev, V., Lu, L., Tsai, H. J., Kim, I. H., Tuteja, D., Mateo, R. K., Singapuri, A., Davis, B. B., Low, R., Hammock, B. D. and Chiamvimonvat, N. : Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors. Proc. Natl. Acad. Sci. USA 103, 18733 (2006).
  11. Morisseau, C., Newman, J. W., Dowdy, D. L., Goodrow, M. H. and Hammock, B. D. : Inhibition of Microsomal Epoxide Hydrolases by Ureas, Amides, and Amines. Chem. Res. Toxicol. 14, 409 (2000).
  12. Caymanchem (Ann arbor, Michigan) : Soluble epoxide hydrolase inhibitor screening assay kit booklet. http:// www.caymanchem.com/pdfs/10011671.pdf.
  13. Huang, S. X., Li, H. Y., Liu, J. Y., Morisseau, C., Hammock, B. D. and Long, Y. Q. : Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties. J. Med. Chem. 53, 8376 (2010).
  14. Pacifici, G. M., Franchi, M., Bencini, C. and Rane, A. : Valpromide inhibits human epoxide hydrolase. Br. J. Clin. Pharmacol. 22, 269 (1986)
  15. Pisani, F., Haj-Yehia, A., Fazio, A., Artesi, C., Oteri, G., Perucca, E., Kroetz, D. L., Levy, R. H. and Bialer, M. : Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation. Epilepsia. 34, 954 (1993).