Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors

Codony, Sandra; Valverde, Elena; Leiva, Rosana; Brea, José; Loza, Marı́a Isabel; Morisseau, Christophe; Hammock, Bruce D.

doi:10.1016/j.bmc.2019.115078

Cited by 17 publications

(15 citation statements)

References 53 publications

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“…Essential drawback of known sEH inhibitors are their fast metabolism under the action of P450 cytochrome and poor water solubility [9]. However, for high inhibitory activity toward sEH, the urea molecule should necessarily contain a highly lipophilic fragment [10].…”

Section: Doi: 101134/s1070428020080023mentioning

confidence: 99%

Synthesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: IV.1 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-(fluoro, chlorophenyl)ureas

2020

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Section: Doi: 101134/s1070428020080023mentioning

confidence: 99%

Synthesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: IV.1 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-(fluoro, chlorophenyl)ureas

2020

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“…Indeed, urea 6 , a diamantane analogue of the well-known sEHI 4 , t -AUCB, and 5 , t -TUCB, showed to be a subnanomolar inhibitor of the human sEH (hsEH) ( Figure 2 ). 11 Therefore, herein we are testing new sEH that merge the adamantyl and phenyl groups in a unique polycyclic scaffold.…”

Section: Introductionmentioning

confidence: 99%

From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis

et al. 2021

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The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

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“…Taking into account that several adamantane-based and benzene-based ureas are endowed with very potent activity as sEHI [14][15][16][17], that both AR9281 and EC5026 feature an acylpiperidine unit, and that the highly hydrophobic pocket of sEH seems able to accommodate very large hydrophobic groups [18], we have recently designed, synthesized and pharmacologically evaluated a novel series of ureas featuring the benzohomoadamantane scaffold as hydrophobic moiety, that merges in its polycyclic structure an adamantane-related core with an aromatic ring [19]. Several of these novel sEHI-based ureas were low nanomolar inhibitors of the human and murine sEH, but most of them, as 1, showed high melting points, limited solubility, and unacceptably low microsomal stabilities (Figure 2) [19].…”

Section: Introductionmentioning

confidence: 99%

2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity

et al. 2021

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The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic substituents limiting their availability. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, a new series of benzohomoadamantane-based amides were synthetized, fully characterized, and evaluated as sEHI. Most of these amides were endowed with excellent inhibitory potencies. A selected compound displayed anti-inflammatory effects with higher effectiveness than the reference sEHI, TPPU.

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Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors

Cited by 17 publications

References 53 publications

Synthesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: IV.1 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-(fluoro, chlorophenyl)ureas

Synthesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: IV.1 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-(fluoro, chlorophenyl)ureas

From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis

2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity

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