Synthesis and biological evaluation of novel (−)-cercosporamide derivatives as potent selective PPARγ modulators

Furukawa, Akihiro; Arita, Tsuyoshi; Fukuzaki, Takehiro; Mori, Makoto; Honda, Takeshi; Satoh, Susumu; Matsui, Yumi; Wakabayashi, Kenji; Hayashi, Shigeru; Nakamura, Kouichi; Araki, Koji; Kuroha, Masanori; Tanaka, Jun; Wakimoto, Satoko; Сузукі, Осаму; Ohsumi, Jun

doi:10.1016/j.ejmech.2012.05.040

Cited by 15 publications

(2 citation statements)

References 26 publications

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“…The use of SPPARMs is considered a new approach for PPARγ‐targeted drugs. Several studies have evaluated SPPARMs in comparison to the established stronger agonists such as rosiglitazone and pioglitazone; however, to date, results have not been able to determine, especially at the molecular level, the characteristics of SPPARM or how to identify an ideal SPPARM. In the present study, we concluded that YR4‐42 is a novel SPPARM based on its PPARγ transactivation activity, PPARγ binding and affinity, and its ability to recruit PPARγ coactivators.…”

Section: Discussionmentioning

confidence: 99%

A novel specific peroxisome proliferator‐activated receptor γ (PPARγ) modulator YR4‐42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet‐induced obese mice

Huan

Pan

Peng

et al. 2019

Diabetes Obesity Metabolism

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AimsTo evaluate a novel tetrahydroisoquinoline derivative YR4‐42 as a selective peroxisome proliferator‐activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti‐diabetic effects in vitro and in vivo.Materials and methodsUsing two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ binding affinity and transactivation action of YR4‐42 were evaluated using biochemical and cell‐based reporter gene assays. The capacity of YR4‐42 to recruit coactivators of PPARγ was also assessed. The effects of YR4‐42 on adipogenesis and glucose consumption and PPARγ Ser273 phosphorylation were investigated in 3T3‐L1 adipocytes. The effects of YR4‐42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high‐fat diet‐induced obese (DIO) C57BL/6J mice. The expression of PPARγ target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo.Results In vitro biochemical and cell‐based functional assays showed that YR4‐42 has much weaker binding affinity, transactivation, and recruitment to PPARγ of the coactivators thyroid hormone receptor‐associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1‐α (PGC1α) compared to full agonists. In 3 T3‐L1 adipocytes, YR4‐42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α‐mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ Ser273 phosphorylation‐dependent genes. Furthermore, in DIO mice, oral administration of YR4‐42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4‐42 also improved hyperlipidaemia‐associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4‐42 appeared to selectively modulate PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4‐42 selectively targets PPARγ‐regulated genes mapped to glucose and lipid metabolism in DIO mice.ConclusionsWe conclude that YR4‐42 is a novel anti‐diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4‐42 should be further investigated in preclinical and clinical studies.

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Section: Discussionmentioning

confidence: 99%

A novel specific peroxisome proliferator‐activated receptor γ (PPARγ) modulator YR4‐42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet‐induced obese mice

Huan

Pan

Peng

et al. 2019

Diabetes Obesity Metabolism

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“…In cross-coupling catalysis, Stille coupling is still aw idely used method. [191] In this section, Ih ighlight the recent applications of Me 4 Sn in CÀCf ormation by using aryl triflates [192] and aryl halides (Ar-I, [193] Ar-Br, [194] and Ar-Cl) [195] as the electrophile substrates. Figure 7s howcases selected C-methylated products and different key conditions.…”

Section: 211m Elimentioning

confidence: 99%

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

Chen

2018

Chemistry A European J

177

121

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Methylation is a well‐known structural modification in organic and medicinal chemistry. This review summarizes recent advances in methylation by categorizing specific methylation reagents. The challenges of mono N‐methylation of aliphatic amines and N‐methylation of peptides are discussed. This review will be useful for chemists wanting to select the appropriate reagents for methylation chemistry. Based on the large diversity of methylation reagents and their wide scope, this review also broadens perspectives on which strategies to select for utilizing a particular methylation, resulting in an increased flexibility in synthetic route planning.

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Advances in the Synthesis of Methylated Products Through Direct Approaches: A Guide for Selecting Methylation Reagents

Chen¹

2022

The Chemical Transformations of C1 Compounds

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Synthesis and biological evaluation of novel (−)-cercosporamide derivatives as potent selective PPARγ modulators

Cited by 15 publications

References 26 publications

A novel specific peroxisome proliferator‐activated receptor γ (PPARγ) modulator YR4‐42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet‐induced obese mice

A novel specific peroxisome proliferator‐activated receptor γ (PPARγ) modulator YR4‐42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet‐induced obese mice

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

Advances in the Synthesis of Methylated Products Through Direct Approaches: A Guide for Selecting Methylation Reagents

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