Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and inadequate patient adherence, resulting in poor management of the disease. Multi-target approaches aim at reducing the polypharmacology and improving the efficacy. This review summarizes the medicinal chemistry efforts to develop multi-target ligands for MetS. Different combinations of pharmacological targets in context of in vivo efficacy and future perspective for multi-target drugs in MetS are discussed.
The retinoid X receptors
(RXR) are ligand-activated transcription
factors involved in multiple regulatory networks as universal heterodimer
partners for nuclear receptors. Despite their high therapeutic potential
in many pathologies, targeting of RXR has only been exploited in cancer
treatment as the currently available RXR agonists suffer from exceptional
lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming
to overcome the limitations and to provide improved RXR ligands, we
developed a new potent RXR ligand chemotype based on the nonsteroidal
anti-inflammatory drug oxaprozin. Systematic structure–activity
relationship analysis enabled structural optimization toward low nanomolar
potency similar to the well-established rexinoids. Cocrystal structures
of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared
to current RXR agonists. The optimized compounds were highly selective
for RXR activation and induced RXR-regulated gene expression in native
cellular and in vivo settings suggesting them as
excellent chemical tools to further explore the therapeutic potential
of RXR.
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.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.