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

Abstract

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.

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

“…Separately and noteworthy, we have recently found in a related series of sEHI that the substitution of the methyl group at C-9 of the polycyclic structure in 11a by halogen atoms, as in 11b and 11c, led to a significative increase in the microsomal stability, particularly in murine microsomes (Table 2) [19].…”

“…The plate was centrifuged (46000 g, 30 min) and supernatants were taken and analyzed in a UPLC-MS/MS (Xevo-TQD, Waters) by employing a BEH C18 column and an isocratic gradient of 0.1% formic acid in water: 0.1% formic acid acetonitrile (60:40). The metabolic stability of the compounds was calculated from the logarithm of the remaining compounds at each of the time points studied [19].…”

“…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]. Taking into account that amides are good pharmacophores for sEHI [20], the aim of the present study was to replace the urea moiety of 1 by an amide group in order to improve the physical properties and, particularly, its very poor microsomal stability to improve availability and in vivo efficacy.…”

Anti-Inflammatory Activity of Soluble Epoxide Hydrolase Inhibitors Based on Selenoureas Bearing an Adamantane Moiety

“…To resolve the existing problems of sEHI, numerous structural modifications were made. Among those modifications were the establishment of the basic structure of inhibitors [8] and various alterations of the lipophilic part of its molecules [7,9,10]. Compound EC5026 (Figure 1) containing the 3-fluoro-4-trifluorometoxyphenyl lipophilic group is in phase I human clinical trials as a new drug candidate intended to treat neuropathic pain [11].…”

A New Family of Subnanomolar inhibitors of Soluble Epoxide Hydrolase

“…However, their very low microsomal stability prevented further development. 3 Herein, novel series of benzohomoadamantane-based ureas were synthesized, fully characterized, and evaluated as sEHI. Most of them were endowed with subnanomolar inhibitory potencies at the human and murine enzymes.…”