4 research outputs found
Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology
Multitarget design
offers access to bioactive small molecules with
potentially superior efficacy and safety. Particularly multifactorial
chronic inflammatory diseases demand multiple pharmacological interventions
for stable treatment. By minor structural changes, we have developed
a close analogue of the cysteinyl-leukotriene receptor antagonist
zafirlukast that simultaneously inhibits soluble epoxide hydrolase
and activates peroxisome proliferator-activated receptor γ.
The triple modulator exhibits robust anti-inflammatory activity in
vivo and highlights the therapeutic potential of designed multitarget
agents
Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology
Multitarget design
offers access to bioactive small molecules with
potentially superior efficacy and safety. Particularly multifactorial
chronic inflammatory diseases demand multiple pharmacological interventions
for stable treatment. By minor structural changes, we have developed
a close analogue of the cysteinyl-leukotriene receptor antagonist
zafirlukast that simultaneously inhibits soluble epoxide hydrolase
and activates peroxisome proliferator-activated receptor γ.
The triple modulator exhibits robust anti-inflammatory activity in
vivo and highlights the therapeutic potential of designed multitarget
agents
<i>N</i>‑Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators
Metabolic syndrome (MetS) is a multifactorial
disease cluster that consists of dyslipidemia, cardiovascular disease,
type 2 diabetes mellitus, and obesity. MetS patients are strongly
exposed to polypharmacy; however, the number of pharmacological compounds
required for MetS treatment can be reduced by the application of multitarget
compounds. This study describes the design of dual-target ligands
that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated
receptor type γ (PPARγ). Simultaneous modulation of sEH
and PPARγ can improve diabetic conditions and hypertension at
once. <i>N</i>-Benzylbenzamide derivatives were determined
to fit a merged sEH/PPARγ pharmacophore, and structure–activity
relationship studies were performed on both targets, resulting in
a submicromolar (sEH IC<sub>50</sub> = 0.3 μM/PPARγ EC<sub>50</sub> = 0.3 μM) modulator <b>14c</b>. In vitro and in vivo evaluations revealed
good ADME properties qualifying <b>14c</b> as a pharmacological
tool compound for long-term animal models of MetS
<i>N</i>‑Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators
Metabolic syndrome (MetS) is a multifactorial
disease cluster that consists of dyslipidemia, cardiovascular disease,
type 2 diabetes mellitus, and obesity. MetS patients are strongly
exposed to polypharmacy; however, the number of pharmacological compounds
required for MetS treatment can be reduced by the application of multitarget
compounds. This study describes the design of dual-target ligands
that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated
receptor type γ (PPARγ). Simultaneous modulation of sEH
and PPARγ can improve diabetic conditions and hypertension at
once. <i>N</i>-Benzylbenzamide derivatives were determined
to fit a merged sEH/PPARγ pharmacophore, and structure–activity
relationship studies were performed on both targets, resulting in
a submicromolar (sEH IC<sub>50</sub> = 0.3 μM/PPARγ EC<sub>50</sub> = 0.3 μM) modulator <b>14c</b>. In vitro and in vivo evaluations revealed
good ADME properties qualifying <b>14c</b> as a pharmacological
tool compound for long-term animal models of MetS