2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis

Abstract

In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammation and pain, suggesting sEH as a pharmacological target for the treatment of inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors but the lipophilicity of the adamantane group compromises their overall solubility. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility of three series of urea-based sEH inhibitors. Most of these oxa-analogs are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics calculations rationalize the basis for their activity and suggest an explanation for their somehow lower activity vs their hydrocarbon counterparts.Biological profiling of novel 2-oxaadamantane-based sEH inhibitors allowed us to select a candidate for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 2-oxaadamantane 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

“…The replacement of adamantyl and 4-(trifluoromethoxy)phenyl groups with natural bicyclic lipophilic groups provided a series of sEHIs with similar potency and 10-fold more water solubility compared to the original compounds [ 82 ]. On a similar note, Codony and coworkers developed 2-oxaadamant-1-yl urea-based molecules and reported that the replacement of a methylene unit of the adamantane group by an oxygen atom increased the solubility, permeability, and stability with nanomolar sEH inhibitory potency [ 83 ]. Pharmacophore-based virtual screening has been used for discovery of 6-amino-2-((4-chlorobenzyl)thio)-5-phenylpyrimidin-4(3H)-one and urea-based potent sEHIs [ 84 ].…”

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

“…Previously, we have shown that less potent inhibitors displayed fluctuations in the interactions between the urea motif and the catalytic residues, shifting the ensemble toward longer distances. 19 All inhibitors share a common scaffold on the RHS of the urea and MD simulations reported a similar behavior in terms of interactions and conformational dynamics in the RHS and central channel regions. The network of hydrogen bonds and π–π stacking interactions is key to retain the inhibitor in the active site.…”

“… 25 Previously, we showed that the active site of EHs present high plasticity. 19 , 26 Available X-ray structures of sEH in complex with adamantyl ureas indicate that the adamantane scaffold can occupy both LHS and RHS pockets. 27 In the case of t -AUCB (PDB: 5AM3), the inhibitor is orientated with the benzoic acid group occupying the RHS, while adamantane sits in the LHS (see Figure 4 ).…”

“… 28 As observed previously, in the apo state, the total volume encompassing LHS, RHS, and the central channel displays wide fluctuations from 70 to 700 Å 3 (average volume 290 ± 133 Å 3 ). 19 The size of the LHS pocket is mainly determined by flexible Ile363, Ile375, Met469, and Asn472 side chains, while the shape of the RHS pocket fluctuates with frequent side chain conformational changes of Leu408, Met419, and Phe497 residues (see Figure S1 ). When t -AUCB, 20 , 22 , and 23 compounds are bound in the active site, an expansion of the active site volume with respect to the average apo value is observed, which becomes stable at around 330–400 Å 3 (see Figures 4 b,c and S1 ).…”

“…Of note, a very recent work has described that the replacement of a methylene unit of the adamantane moiety by an oxygen atom led to more soluble compounds while only slightly reducing the inhibitory activity against the sEH (e.g., 1b, 4b, and 7b in Figure 3). 19 In this sense, an oxygen atom was introduced in the benzohomoadamantane scaffold in order to explore whether a similar trend was also followed within this new family of sEHIs (Figure 3 and Scheme 1).…”