Discovery of a Highly Potent, Selective, and Bioavailable Soluble Epoxide Hydrolase Inhibitor with Excellent Ex Vivo Target Engagement

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

doi:10.1021/jm900725r

Cited by 40 publications

(30 citation statements)

References 19 publications

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“…52 The ability of sEHIs to protect the brain from injury in cardiovascular disease is due to its dual action to improve vascular function and remodeling and by protecting the neurons from cell death. 52,64,65 Taken together these studies demonstrate that sEHI has the ability to protect organs from injury in hypertension and relates to actions not only on blood vessels but other cell types.…”

Section: Soluble Epoxide Hydrolase Inhibitorsmentioning

confidence: 76%

Targeting Epoxides for Organ Damage in Hypertension

Imig¹

2010

Journal of Cardiovascular Pharmacology

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Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid and EETs have a number of beneficial cardiovascular actions. This has led to the concept that EETs and its metabolic pathway can be therapeutically targeted for hypertension and other cardiovascular diseases. One approach has been to prevent the conversion of EETs to their inactive diols by inhibiting the soluble epoxide hydrolase (sEH) enzyme. Inhibition of sEH has been demonstrated to decrease blood pressure in certain experimental models of hypertension, decrease inflammation, and protect organs from damage associated with hypertension and other cardiovascular diseases. The development of sEH inhibitors has reached the point where they are being evaluated in humans. A second therapeutic approach has been to develop EET agonists. EET agonists have been essential for determining the structure function relationship for EETs and determining cell-signaling mechanisms by which EETs exert their cardiovascular actions. More recently, EET agonists have been administered chronically to experimental animal models of hypertension and metabolic syndrome and have been demonstrated to decrease blood pressure, improve insulin signaling, and improve vascular function. These experimental findings provide evidence for sEH inhibitors and EET agonists as a therapeutic approach for cardiovascular diseases, hypertension, and the associated end organ damage.

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Section: Soluble Epoxide Hydrolase Inhibitorsmentioning

confidence: 76%

Targeting Epoxides for Organ Damage in Hypertension

Imig¹

2010

Journal of Cardiovascular Pharmacology

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“…Other laboratories 25 have developed highly potent sEH-inhibitors that utilize ureas as the epoxide bioisostere. Similar functionality appears in some of our 17,18-EETeTr agonists, e.g., 19 (Table 2).…”

Section: Resultsmentioning

confidence: 99%

17(R),18(S)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure–Activity Relationships and Stable Analogues

et al. 2011

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17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca2+-overload with an EC50 ~1–2 nM. Structure-activity studies revealed a cis-Δ11,12- or Δ14,15-olefin and a 17(R),18(S)-epoxide are minimal structural elements for anti-arrhythmic activity whereas antagonist activity was often associated with the combination of a Δ14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogs are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.

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“…Tedious formation such as the use of nanocrystals from cryomilling with careful selection of salts and solvents are needed to formulate such materials for efficient delivery in a small capsule (Ghosh et al, 2008). As an alternative to such formulation approaches, a medicinal chemistry approach was taken to develop new potent inhibitors that are more water-soluble and more metabolically stable by methodically modifying their structures (Zhao et al, 2004; Hwang et al, 2006; Jones et al, 2006; Li et al, 2006; Morisseau et al, 2006; Hwang et al, 2007; Kim et al, 2007a; Kim et al, 2007b; Kasagami et al, 2009; Shen et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Tsai

Hwang

Morisseau

et al. 2010

European Journal of Pharmaceutical Sciences

143

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Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N’-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1 mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.

show abstract

Discovery of a Highly Potent, Selective, and Bioavailable Soluble Epoxide Hydrolase Inhibitor with Excellent Ex Vivo Target Engagement

Cited by 40 publications

References 19 publications

Targeting Epoxides for Organ Damage in Hypertension

Targeting Epoxides for Organ Damage in Hypertension

17(R),18(S)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure–Activity Relationships and Stable Analogues

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

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