Design, Synthesize and Biological Evaluation of Novel Urea Soluble Epoxide Hydrolase Inhibitors

Document Type : Research Article

Authors

1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, I.R. IRAN

2 Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, I.R. IRAN

Abstract

Soluble Epoxide Hydrolase (sEH) enzyme converts Epoxyeicosatrienoic acids (EETs), substrates formed by epoxygenases from arachidonic acid, to the corresponding diols. EETs have a wide range of physiological effects. Among them, vasodilatory actions in vascular conduit, renal afferent arterioles, and coronary vessels are more considerable and lead to the regulation of blood pressure and myocardial perfusion. In addition, EETs modulate adhesion molecule expression, platelet aggregation, vascular smooth muscle cell migration, and thrombolytic properties, which could be involved in a protective mechanism against athero 5 sclerosis. Therefore, sEH inhibition that leads to the accumulation of active EETs, provides a novel approach to the treatment of hypertension and atherosclerosis. Since the most reported potent sEH inhibitors have limited pharmacokinetic profile, they aren’t useful for clinical application. The effort to achieve to sEH inhibitors with proper potency and enhanced pharmacokinetic properties is still continuous. In this study, new urea-based compounds with oxadiazole ring against sEH enzyme were developed.
The designed compounds showed a high affinity to the active site of the sEH enzyme and were synthesized in good yield and characterized by IR, Mass, and 1HNMR. Some novel compounds had comparable in vitro sEH inhibitory activity to 12-(3-Adamantan-1-yl-ureido)-dodecanoicacid (AUDA), a potent urea-based sEH inhibitor.

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References

[1] Miyamoto T., Silva M., Hammock B.D., Inhibition of Epoxide Hydrolases and Glutathione S-transferases by 2-, 3-, and 4-Substituted Derivatives of 4′-Phenylchalcone and its Oxide. Arch Biochem Biophys, 254 (1): 203-13 (1987).
[2] Dietze E.C., Kuwano E., Casas J., Hammock B.D., Inhibition of Cytosolic Epoxide Hydrolase by trans-3-Phenylglycidols. Biochem Pharmacol, 42 (6): 1163-75 (1991).
[3] Pecic S., Pakhomova S., Newcomer M.E., Morisseau C., Hammock B.D., Zhu Z., Synthesis and Structure–Activity Relationship of Piperidine-Derived Non-Urea Soluble Epoxide Hydrolase Inhibitors. Bioorg Med Chem Lett; 23 (2): 417-21 (2013).
[4] Shen H.C., Ding F.X., Wang S., Xu S., Chen H.S., Tong X., Discovery of Spirocyclic Secondary Amine-Derived Tertiary Ureas as Highly Potent, Selective and Bioavailable Soluble Epoxide Hydrolase Inhibitors. Bioorg Med Chem Lett, 19 (13): 3398-404(2009).
[5] Xie Y., Liu Y., Gong G., Smith D.H., Yan F., Rinderspacher A., Discovery of Potent Non-Urea Inhibitors of Soluble Epoxide Hydrolase. Bioorg Med Chem Lett, 19 (8): 2354-9 (2009).
[6] Huang S.X., Li H.Y., Liu J.Y., Morisseau C., Hammock B.D., 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 (23): 8376-86 (2010).
[7] Kim I.H., Tsai H.J., Nishi K., Kasagami T., Morisseau C., Hammock B.D., 1,3-Disubstituted Ureas Functionalized with Ether Groups are Potent Inhibitors of the Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties. J Med Chem, 50 (21): 5217-26 (2007).
[8] Shen H.C., Ding F.X., Wang S., Deng Q., Zhang X., Chen Y., Discovery of a Highly Potent, Selective, and Bioavailable Soluble Epoxide Hydrolase Inhibitor with Excellent Ex vivo Target Engagement. J Med Chem, 52 (16): 5009-12 (2009).
[9] Shen H.C., Ding F.X., Deng Q., Xu S., Tong X., Zhang X., A Strategy of Employing Aminoheterocycles as Amide Mimics to Identify Novel, Potent and Bioavailable Soluble Epoxide Hydrolase Inhibitors. Bioorg Med Chem Lett; 19 (19): 5716-21(2009).
[10] ضیایی، عظیم آقابزرگ نانوا، پریچهر؛ لطفی نوسود، یزدان بخش؛ خلیلی، بهزاد؛ تهیه 4 - آریلیدین - 2 - آلکیل تیو - 4H - تیازول - 5 - اون ها با استفاده از آمینواسید های دی تیوکاربامات و آلدهید ها، نشریه شیمی و مهندسی شیمی ایران، 35 (3( : 43-55 (1395)
[11] Schiøtt B., Bruice T.C., Reaction Mechanism of Soluble Epoxide Hydrolase: Insights from Molecular Dynamics Simulations . J Am Chem Soc, 124 (49): 14558-70 (2002).
[12] Morisseau C., Goodrow M.H., Newman J.W., Wheelock C.E., Dowdy D.L., Hammock B.D., Structural Refinement of Inhibitors of Urea-Based Soluble Epoxide Hydrolases. Biocheml pharmacol, 63(9): 1599-608(2002).
[13] Kim I.H., Nishi K., Tsai H.J., Bradford T., Koda Y., Watanabe T., Morisseaua C., Blanchfield J., Toth I., Hammock B.D. , A Design of Bioavailable Derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a Potent Inhibitor of the Soluble Epoxide Hydrolase. Bioorg Med Chem, 15 (1): 312-23(2007).
[14] Anandan S.K., Webb H.K., Chen D., Wang Y.X., Aavula B.R., Cases S., 1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a Potent, Selective, and Orally Available Soluble Epoxide Hydrolase Inhibitor with Efficacy in Rodent Models of Hypertension and Dysglycemia. Bioorg Med Chem Lett; 21 (3): 983-8(2011).
[15] Pecic S., Deng S.X., Morisseau C., Hammock B.D., Landry D.W., Design, Synthesis and Evaluation of Non-Urea Inhibitors of Soluble Epoxide Hydrolase. Bioorg Med Chem Lett, 22 (1): 601-5 (2012).
[16] Kim I.H., Heirtzler F.R., Morisseau C., Nishi K., Tsai H.J., Hammock B.D., Optimization of Amide-Based Inhibitors of Soluble Epoxide Hydrolase with Improved Water Solubility. J Med Chem, 48 (10): 3621 (2005).
[17] Anandan S.K., Do Z.N., Webb H.K., Patel D.V., Gless R.D., Non-urea Functionality as the Primary Pharmacophore in Soluble Epoxide Hydrolase Inhibitors. Bioorg Med Chem Lett, 19 (4): 1066-70 (2009).
[18] Anandan S.K., Gless R. D., Exploration of Secondary and Tertiary Pharmacophores in Unsymmetrical N,N′-diaryl Urea Inhibitors of Soluble Epoxide Hydrolase. Bioorg Med Chem Lett, 20 (9): 2740-4 (2010).
[19] Li HY., Jin Y., Morisseau C., Hammock B. D., Long Y. Q., The 5-Substituted Piperazine as a Novel Secondary Pharmacophore Greatly Improving the Physical Properties of Urea-Based Inhibitors of Soluble Epoxide Hydrolase. Bioorg Med Chem, 14 (19): 6586-92 (2006).
[20] Rezaee Zavareh E., Hedayati M., Hoghooghi Rad L., Kiani A., Shahhosseini S., Faizi M., Tabatabai S.A., Design, Synthesis and Biological Evaluation of Some Oxadiazole Derivatives as Novel Amide-Based Inhibitors of Soluble Epoxide Hydrolase. Lett Drug Des Discovery, 11 (6): 721-730 (2014).
[21] Rezaee Zavareh E., Hedayati M., Hoghooghi Rad L., Shahhosseini S., Faizi M., Tabatabai S.A., Design, Synthesis and Biological Evaluation of 4-Benzamidobenzoic Acid Hydrazide Derivatives as Novel Soluble Epoxide Hydrolase Inhibitors. Iranian J Pharm Res, 13 (Suppl): 51-59 (2014).
[22] Rezaee E., Hedayati M., Hoghooghi Rad L., Shahhosseini S., Faizi M., Tabatabai S.A., Novel Soluble Epoxide Hydrolase Inhibitors with a Dihydropyrimidinone Scaffold: Design, Synthesis and Biological Evaluation, Med Chem Comm, 7 (11): 2128-35 (2016).
[23] Faizi M., Sheikhha M., Ahangar N., Ghomi HT., Shafaghi B., Shafiee A., Tabatabai S.A., Design, Synthesis and Pharmacological Evaluation of Novel 2-[2-(2-chlorophenoxy) phenyl]-1, 3, 4-Oxadiazole Derivatives as Benzodiazepine Receptor Agonists. Iranian J Pharm Res, 11(1): 83-90 (2012).
[24] Naimi-Jamal M. R., Mokhtari J., Gorban Dekamin M., Javanshir S., Hamzeali H., Efficient Synthesis and Deprotection of Semicarbazones under Solvent-Free Conditions. Iran. Chem. Chem. Eng.(IJCCE), 31(2): 1-8 (2012).

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