Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast

Schierle, Simone; Helmstädter, Moritz; Schmidt, Jurema; Hartmann, Markus; Horz, Maximiliane; Kaiser, Astrid; Weizel, Lilia; Heitel, Pascal; Proschak, Anna; Hernández‐Olmos, Víctor; Proschak, Ewgenij; Merk, Daniel

doi:10.1002/cmdc.201900576

Cited by 14 publications

(15 citation statements)

References 44 publications

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“…Recently, dual FXR activators/sEH inhibitors have been reported that are derived from the antiasthma drug Zafirlukast. These inhibitors possess favorable dual potency towards FXR and sEH while reducing the original cysteinyl leukotriene receptor antagonism of the lead drug [ 148 ]. Inceoglu and coworkers demonstrated that coadministration of phosphodiesterase 4 (PDE4) and sEH inhibitors results in an enhanced analgesic effect compared to the individual treatments [ 149 ].…”

Section: Dual Inhibition/modulation Of Seh As Part Of Anti-inflammmentioning

confidence: 99%

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

2020

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The enzyme soluble epoxide hydrolase (sEH) plays a central role in metabolism of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH converts epoxyeicosatrienoic acids (EETs) to less bioactive dihydroxyeicosatrienoic acids. EETs exhibit anti-inflammatory, analgesic, antihypertensive, cardio-protective and organ-protective properties. Accordingly, sEH inhibition is a promising therapeutic strategy for addressing a variety of diseases. In this review, we describe small molecule architectures that have been commonly deployed as sEH inhibitors with respect to angiogenesis, inflammation and cancer. We juxtapose commonly used synthetic scaffolds and natural products within the paradigm of a multitarget approach for addressing inflammation and inflammation induced carcinogenesis. Structural insights from the inhibitor complexes and novel strategies for development of sEH-based multitarget inhibitors are also presented. While sEH inhibition is likely to suppress inflammation-induced carcinogenesis, it can also lead to enhanced angiogenesis via increased EET concentrations. In this regard, sEH inhibitors in combination chemotherapy are described. Urea and amide-based architectures feature prominently across multitarget inhibition and combination chemotherapy applications of sEH inhibitors.

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Section: Dual Inhibition/modulation Of Seh As Part Of Anti-inflammmentioning

confidence: 99%

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

2020

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“…Zafirlukast: Schierle et al, in their study, derive a compound from zafirlukast that has the ability to interact with farnesoid X receptor and soluble epoxide hydrolase (FXRA/sEHi). The combination of which can prove to be a potential therapeutic target in the treatment of metabolic syndrome and NASH [ 22 ]. The farnesoid X receptor when activated has the ability to decrease hepatic steatosis and fibrosis which has been implicated in the development of NASH as one of the key pathological changes.…”

Section: Reviewmentioning

confidence: 99%

“…The farnesoid X receptor when activated has the ability to decrease hepatic steatosis and fibrosis which has been implicated in the development of NASH as one of the key pathological changes. This activity of NASH is brought about by Zafirlukast-derived FXRA/sEHi 13 and 16 [ 22 ]. The sEH in turn has exhibited a strong anti-inflammatory effect which can be the turning point in the treatment of NASH.…”

Section: Reviewmentioning

confidence: 99%

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Treatment of Fatty Liver Disease: The Present and the Future

Ramanan

Mohamed

Aung

et al. 2021

Cureus

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Non-alcoholic fatty liver disease (NAFLD) progressing to non-alcoholic steatohepatitis (NASH), cirrhosis, end-stage liver disease (ESRD), and hepatocellular carcinoma (HCC) is emerging as a global epidemic. Obesity, diabetes, and metabolic syndrome are some of the leading risk factors for NAFLD. The most prevalent treatment to stop the progression is aimed at dietary modification and lifestyle changes. Bariatric surgery is indicated for patients with morbid obesity with NAFLD. The progression of NAFLD to NASH and HCC can be arrested at various stages of pathogenesis by the already prevalent drugs and the emerging newer molecular and genetic targets. This review article analyzed various preclinical animal trials and clinical trials and has summarized various groups of drugs that can be life-altering in patients diagnosed with NAFLD. This study also discusses the obstacles in taking these clinical trials to bedside treatment.

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“…Designed polypharmacology addressing complementary pathomechanisms may, therefore, offer access to synergistic efficacy in this complex disease. Following this strategy, we have previously developed dual modulators to target, for example, farnesoid X receptor (FXR) and soluble epoxide hydrolase (sEH),[ 6 , 7 , 8 ] or FXR and peroxisome proliferator‐activated receptors (PPARs). [ 9 , 10 ] Strong therapeutic efficacy of such multi‐target agents in preclinical NASH models[ 10 , 11 ] corroborates the potential of designed polypharmacology in this indication.…”

Section: Introductionmentioning

confidence: 99%

Development and in vitro Profiling of Dual FXR/LTA4H Modulators

et al. 2021

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Designed polypharmacology presents as an attractive strategy to increase therapeutic efficacy in multi‐factorial diseases by a directed modulation of multiple involved targets with a single molecule. Such an approach appears particularly suitable in non‐alcoholic steatohepatitis (NASH) which involves hepatic steatosis, inflammation and fibrosis as pathological hallmarks. Among various potential pharmacodynamic mechanisms, activation of the farnesoid X receptor (FXRa) and inhibition of leukotriene A4 hydrolase (LTA4Hi) hold promise to counteract NASH according to preclinical and clinical observations. We have developed dual FXR/LTA4H modulators as pharmacological tools, enabling evaluation of this polypharmacology concept to treat NASH and related pathologies. The optimized FXRa/LTA4Hi exhibits well‐balanced dual activity on the intended targets with sub‐micromolar potency and is highly selective over related nuclear receptors and enzymes rendering it suitable as tool to probe synergies of dual FXR/LTA4H targeting.

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Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast

Cited by 14 publications

References 44 publications

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Treatment of Fatty Liver Disease: The Present and the Future

Development and in vitro Profiling of Dual FXR/LTA4H Modulators

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