The emerging pharmacological
target soluble epoxide hydrolase (sEH)
is a bifunctional enzyme exhibiting two different catalytic activities
that are located in two distinct domains. Although the physiological
role of the C-terminal hydrolase domain is well-investigated, little
is known about its phosphatase activity, located in the N-terminal
phosphatase domain of sEH (sEH-P). Herein we report the discovery
and optimization of the first inhibitor of human and rat sEH-P that
is applicable in vivo. X-ray structure analysis of the sEH phosphatase
domain complexed with an inhibitor provides insights in the molecular
basis of small-molecule sEH-P inhibition and helps to rationalize
the structure–activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic
acid (22b, SWE101) has an excellent pharmacokinetic and
pharmacodynamic profile in rats and enables the investigation of the
physiological and pathophysiological role of sEH-P in vivo.
Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation-and fibrosis-related disease models.
Polypharmaceutical regimens often
impair treatment of patients
with metabolic syndrome (MetS), a complex disease cluster, including
obesity, hypertension, heart disease, and type II diabetes. Simultaneous
targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated
receptor γ (PPARγ) synergistically counteracted MetS in
various in vivo models, and dual sEH inhibitors/PPARγ
agonists hold great potential to reduce the problems associated with
polypharmacy in the context of MetS. However, full activation of PPARγ
leads to fluid retention associated with edema and weight gain, while
partial PPARγ agonists do not have these drawbacks. In this
study, we designed a dual partial PPARγ agonist/sEH inhibitor
using a structure-guided approach. Exhaustive structure–activity
relationship studies lead to the successful optimization of the designed
lead. Crystal structures of one representative compound with both
targets revealed potential points for optimization. The optimized
compounds exhibited favorable metabolic stability, toxicity, selectivity,
and desirable activity in adipocytes and macrophages.
Increasing antimicrobial resistance evolves to be one of the major threats to public health. To reduce the selection pressure and thus to avoid a fast development of resistance, novel approaches...
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