Urate transporter inhibitor lesinurad is a selective peroxisome proliferator-activated receptor gamma modulator (sPPARγM) in vitro

Heitel, Pascal; Gellrich, Leonie; Heering, Jan; Goebel, Tamara; Kahnt, Astrid S.; Proschak, Ewgenij; Schubert‐Zsilavecz, Manfred; Merk, Daniel

doi:10.1038/s41598-018-31833-4

Cited by 14 publications

(18 citation statements)

References 55 publications

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“…Differential binding modes within the FXR ligand binding site of FXR agonists OCA and MFA-1 15 , and differential effects of FXR agonists GW4064, CDCA and fexaramine on FXR regulated gene expression 16 already indicated several years ago, that FXR activation is more complex than just switched on or off. Later studies revealed that FXR ligands can differ in their recruitment profiles of various co-activators 17,18 , a characteristic that has also been observed for other NRs such as peroxisome proliferator-activated receptors 19,20 . Moreover, ivermectin 18 and structural analogues 21 were identified as specific FXR modulators that despite recruiting the NR co-repressor NCoR-2 to the FXR-LBD induced FXR-mediated reporter activity and gene expression, and recent results also point to an allosteric mechanism 22 of FXR activation by small molecules.…”

Section: Introductionmentioning

confidence: 71%

Molecular tuning of farnesoid X receptor partial agonism

et al. 2019

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The bile acid-sensing transcription factor farnesoid X receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice. Here we report the elucidation of the molecular mechanism that drives partial FXR activation by crystallography- and NMR-based structural biology. Natural and synthetic FXR agonists stabilize formation of an extended helix α11 and the α11-α12 loop upon binding. This strengthens a network of hydrogen bonds, repositions helix α12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in helix α11 that destabilizes the α11-α12 loop, a critical determinant for helix α12 orientation. Thereby, the synthetic partial agonist induces conformational states, capable of recruiting both co-repressors and co-activators leading to an equilibrium of co-activator and co-repressor binding.

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Section: Introductionmentioning

confidence: 71%

Molecular tuning of farnesoid X receptor partial agonism

et al. 2019

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“…The results showed that SY could also increase PPARc2 mRNA levels in the adipocytes differentiated from the subcutaneous SVF, but not in the adipocytes differentiated from visceral SVF ( Figure S5c,d). These show that SY could be a novel PPARc agonist that might selectively activate PPARc2 in sWAT to improve insulin sensitivity, which could be similar to the selective PPARc modulators 41 . It was reported by Heitel et al 41 that selective PPARc modulators activated PPARc in a tissue-selectivity manner or differentially recruited coactivators to the nuclear receptor in different tissues.…”

Section: Discussionmentioning

confidence: 88%

Safflower yellow improves insulin sensitivity in high‐fat diet‐induced obese mice by promoting peroxisome proliferator‐activated receptor‐γ2 expression in subcutaneous adipose tissue

Yan

Wang

Zhu

et al. 2020

J of Diabetes Invest

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Aims/Introduction Safflower yellow (SY) and its main component, hydroxysafflor yellow A, have been demonstrated to show anti‐obesity effects. Peroxisome proliferator‐activated receptor‐γ2 (PPARγ2) is a critical transcription factor in adipose tissue metabolism. The aim of the present study was to explore the effects of SY in high‐fat diet‐induced obese mice, and further investigate the mechanism involving PPARγ2. Methods High‐fat diet‐induced obese mice were given 120 mg/kg/day SY for 8 weeks. Glucose and insulin tolerance tests were carried out. Fat mass and serum levels of glucose and insulin were measured. The expression of insulin signaling pathway‐related genes and PPARγ2 in the adipose tissue was measured. In vitro , the effects of SY (0–500 mg/L) and hydroxysafflor yellow A (0–100 mg/L) on PPARγ2 promoter activities and PPARγ2 messenger ribonucleic acid (mRNA) levels in 3T3‐L1 preadipocytes or adipocytes were also detected. Results Safflower yellow reduced fat mass, decreased glucose levels and improved insulin sensitivity in obese mice. SY also increased the mRNA levels of insulin signaling pathway‐related genes, and increased PPARγ2 mRNA levels by 39.1% in subcutaneous adipose tissue ( P < 0.05). In vitro , SY and hydroxysafflor yellow A significantly enhanced PPARγ2 promoter activities by 1.3–2.1‐fold, and increased PPARγ2 mRNA levels by 1.2–1.6‐fold in 3T3‐L1 preadipocytes or adipocytes ( P < 0.05). Conclusions SY could reduce fat mass, decrease glucose levels and improve insulin sensitivity in high‐fat diet‐induced obese mice. The probable mechanism is to increase PPARγ2 expression by stimulating PPARγ2 promoter activities, further increasing the expression of insulin signaling pathway‐related genes in subcutaneous adipose tissue.

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“…Lesinurad (Fig. 1) is a medicine prescribed as a urate transporter inhibitor for treating hyperuricemia associated with gout (Heitel et al, 2018). The drug is a weak carboxylic acid (pK a = 3.2).…”

Section: Introductionmentioning

confidence: 99%

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

Palanisamy

Sanphui

Prakash

et al. 2019

Acta Crystallogr C Struct Chem

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Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C 17 H 14 BrN 3 O 2 S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High-throughput solid-form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH 3 OH) and ethanol (C 2 H 5 OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7trimethyl-1H-purine-2,6-dione, C 8 H 10 N 4 O 2 ) and nicotinamide (C 6 H 6 N 2 O), polymorphs with urea (CH 4 N 2 O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT-IR. The crystal structures were solved by single-crystal and powder X-ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid-triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid-triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid-triazole heterosynthon is replaced by an acidamide synthon. Among the urea cocrystal polymorphs, Form I (P1, 1:1) consists of an acid-amide (urea) heterodimer, whereas in Form II (P2 1 /c, 2:2), both acidamide heterosynthons and urea-urea dimers co-exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad-urea Form I (43-fold) > lesinurad-caffeine (20-fold) > lesinurad-allopurinol (12-fold) ' lesinurad-nicotinamide (11-fold) > lesinurad, and this order is correlated with the crystal structures.

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Urate transporter inhibitor lesinurad is a selective peroxisome proliferator-activated receptor gamma modulator (sPPARγM) in vitro

Cited by 14 publications

References 55 publications

Molecular tuning of farnesoid X receptor partial agonism

Molecular tuning of farnesoid X receptor partial agonism

Safflower yellow improves insulin sensitivity in high‐fat diet‐induced obese mice by promoting peroxisome proliferator‐activated receptor‐γ2 expression in subcutaneous adipose tissue

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

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