Spirocyclic
scaffolds are incorporated in various approved drugs
and drug candidates. The increasing interest in less planar bioactive
compounds has given rise to the development of synthetic methodologies
for the preparation of spirocyclic scaffolds. In this Perspective,
we summarize the diverse synthetic routes to obtain spirocyclic systems.
The impact of spirocycles on potency and selectivity, including the
aspect of stereochemistry, is discussed. Furthermore, we examine the
changes in physicochemical properties as well as in in vitro and in
vivo ADME using selected studies that compare spirocyclic compounds
to their nonspirocyclic counterparts. In conclusion, the value of
spirocyclic scaffolds in medicinal chemistry is discussed.
Over the last two decades polypharmacology has emerged as a new paradigm in drug discovery, even though developing drugs with high potency and selectivity toward a single biological target is still a major strategy. Often, targeting only a single enzyme or receptor shows lack of efficacy. High levels of inhibitor of a single target also can lead to adverse side effects. A second target may offer additive or synergistic effects to affecting the first target thereby reducing on-and off-target side effects. Therefore, drugs that inhibit multiple targets may offer a great potential for increased efficacy and reduced the adverse effects. In this review we summarize recent findings of rationally designed multitarget compounds that are aimed to improve efficacy and safety profiles compared to those that target a single enzyme or receptor. We focus on dual inhibitors/modulators that target the soluble epoxide hydrolase (sEH) as a common part of their design to take advantage of the beneficial effects of sEH inhibition.
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.
Multitarget anti-inflammatory drugs interfering with
the arachidonic
acid cascade exhibit superior efficacy. In this study, a prototype
dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward
both targets has been designed and synthesized. Preliminary structure–activity
relationship studies were performed to identify optimal substitution
patterns. X-ray structure analysis of a promising dual inhibitor in
complex with sEH, as well as molecular docking with LTA4H provided a rationale for further optimization. Hereby, scaffold
extension was successfully applied to yield potent dual sEH/LTA4H inhibitors. The spectrum of pro- and anti-inflammatory lipid
mediators was evaluated in M1 and M2 macrophages, stimulated with
LPS, and incubated with the most promising compound 14. The effect of 14 on the inflammatory lipid mediator
profile characterizes dual sEH/LTA4H inhibitors as an interesting
option for future anti-inflammatory agent investigations.
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