Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement

Journal of Medicinal Chemistry

Volumn 52, Issue 16, 2009, Pages 5009-5012

  Shen, Hong C ^a   Ding, Fa Xiang ^a   Wang, Siyi ^a   Deng, Qiaolin ^a   Zhang, Xiaoping ^a   Chen, Yuli ^a   Zhou, Gaochao ^a   Xu, Suoyu ^a   Chen, Hsuan Shen ^a   Tong, Xinchun ^a   Tong, Vincent ^a   Mitra, Kaushik ^a   Kumar, Sanjeev ^a   Tsai, Christine ^a   Stevenson, Andra S ^a   Pai, Lee Yuh ^a   Alonso Galicia, Magdalena ^a   Chen, Xiaoli ^a   Soisson, Stephen M ^a   Roy, Sophie ^a   Zhang, Bei ^a   Tata, James R ^a   Berger, Joel P ^a   Colletti, Steven L ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME INHIBITOR; EPOXIDE HYDROLASE; EPOXIDE HYDROLASE INHIBITOR; PIPERIDINE DERIVATIVE; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ANIMAL TISSUE; ANTIHYPERTENSIVE ACTIVITY; ARTICLE; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG SPECIFICITY; ENZYME INHIBITION; HUMAN; IC 50; MESENTERIC ARTERY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; VASODILATATION;

ANIMALS; BIOLOGICAL AVAILABILITY; CELL LINE; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 ENZYME SYSTEM; EICOSANOIDS; EPOXIDE HYDROLASES; EPOXY COMPOUNDS; HUMANS; ION CHANNELS; KIDNEY; MESENTERIC ARTERIES; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MUSCLE RELAXATION; MUSCLE, SMOOTH, VASCULAR; PIPERIDINES; RATS; RATS, INBRED SHR; SOLUBILITY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 69049113954     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900725r     Document Type: Article

References (21)

1. (a) Newman, J. W.; Morisseau, C.; Hammock, B. D. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog. Lipid Res. 2005, 44, 1-51.
2. (b) Hammock, B. D.; Storms, D. H.; Grant, D. F. Epoxide Hydrolases. In Comprehensive Toxicology; Guengerich, F. P., Ed.; Pergamon: Oxford, U.K., 1997; Vol. 3, pp 283-305.
3. Fretland, A. J.; Omiecinski, C. J. Epoxide hydrolases: biochemistry and molecular biology. Chem.-Biol. Interact. 2000, 129, 41-59.
4. (a) Spector, A. A.; Fang, X.; Snyder, G. D.; Weintraub, N. L. Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog. Lipid Res. 2004, 434, 55-90.
5. (b) Larsen, B. T.; Gutterman, D. D.; Hatoum, O. A. Emerging role of epoxyeicotrienoic acids in coronary vascular function. Eur. J. Clin. Invest. 2006, 36, 293-300.
6. ca channels: implications for soluble epoxide hydrolase inhibition. Am. J. Physiol.: Heart Circ. Physiol. 2006, 290, H491-H499.
7. Archer, S. L.; Gragasin, F. S.; Wu, X.; Wang, S.; McMurty, S.; Kim, D. H.; Platonov, M.; Koshal, A.; Hashimoto, K.; Campbell, W. B.; Falck, J. R.; Michelakis, E. D. Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BK (Ca) channels. Circulation 2003, 107, 769-776.
8. Node, K.; Huo, Y.; Ruan, X.; Yang, B.; Spiecker, M.; Ley, K.; Zeldin, D. C.; Liao, J. K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 1999, 285, 1276-1279.
9. Kessler, P.; Popp, R.; Busse, R.; Schini-Kerth, V. B. Proinflammatory mediators chronically downregulate the formation of the endothelium-derived hyperpolarizing factor in arteries via a nitric oxide/cyclic GMP-dependent mechanism. Circulation 1999, 99, 1878-1884.
10. Imig, J. D.; Zhao, X.; Zaharis, C. Z.; Olearczyk, J. J.; Pollock, D. M.; Newman, J. W.; Kim, I.-H.; Watanabe, T.; Hammock, B. D. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension. Hypertension 2005, 46, 975-981.
11. Yu, Z.; Xu, F.; Huse, L. A.; Morisseau, C.; Draper, A. J.; Newman, J. W.; Parker, C.; Graham, L.; Engler, M. M.; Hammock, B. D.; Zeldin, D. C.; Droetz, D. L. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ. Res. 2000, 87, 992-998.
12. http://www.aretetherapeutics.com.
13. Hwang, S. H.; Tsai, H.-J.; Liu, J.-Y.; Morisseau, C.; Hammock, B. D. Orally bioavailable potent soluble epoxide hydrolase inhibitors. J. Med. Chem. 2007, 50, 3825-3840.
14. Morisseau, C.; Newman, J. W.; Dowdy, D. L.; Goodrow, M. H.; Hammock, B. D. Inhibition of microsomal epoxide hydrolases by ureas, amides and amines. Chem. Res. Toxicol. 2001, 14, 409-415.
15. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: highlights and hang-ups. J. Med. Chem. 2006, 49, 5029-5046 and references therein .
16. Fisslthaler, B.; Hinsch, N.; Chataigneau, T.; Popp, R.; Kiss, L.; Busse, R.; Fleming, I. Nifedipine increases cytochrome P4502C expression and endothelium-derived hyperpolarizing factor-mediated responses in coronary arteries. Hypertension 2000, 36, 270-275.
17. Viswanathan, P. C.; Balser, J. R. Inherited sodium channelopathies: a continuum of channel dysfunction. Trends Cardiovasc. Med. 2004, 14, 28-35.
18. Gomez, G. A.; Morisseau, C.; Hammock, B. D.; Christianson, D. W. Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids. Protein Sci. 2006, 15, 58-64.
19. Holck, M. I.; Jones, C. H. M.; Haeusler,G. Differential interaction of clonidine and methoxamine with the postsynaptic α-adrenoceptor of rabbit main pulmonary artery. J. Cardiovasc. Pharmacol. 1983, 5, 240-248.
20. Campbell, W. B.; Gebremedhin, D.; Pratt, P. F.; Harder, D. R. Indentification of epxoyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 1996, 78, 415-423 and references therein.
21. McGiff, J. C.; Quilley, J. 20-HETE and the kidney: resolution of old problems and new beginnings. Am. J. Physiol. 1999, 277, R607-R623.