A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: Design and synthesis of benzylpyrazole acylsulfonamides

Rikimaru, Kentaro; Wakabayashi, Tomonari; Abe, Hidenori; H, Ito; Maekawa, Taira; Ujikawa, Osamu; Murase, Kouhei; Matsuo, Taisuke; Matsumoto, Mitsuharu; Nomura, Chisako; Tsuge, Hiroko; Arimura, Naoto; Kawakami, Kazutoshi; Sakamoto, Junichi; Funami, Miyuki; Mol, Clifford D.; Snell, G.; Bragstad, Kenneth A.; Sang, Bi‐Ching; Dougan, D.R.; Tanaka, Toshimasa; Katayama, Nozomi; Horiguchi, Yoshiaki; Momose, Yū

doi:10.1016/j.bmc.2011.12.008

Cited by 39 publications

(22 citation statements)

References 33 publications

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“…In recent years, there has been increased interest in this area of research and new novel PPAR-g agonists are under development to replace the 'dying' drug class that is the glitazones. The majority of these are aimed at the improvement of insulin sensitivity and metabolic profile (Cho et al, 2011;Chaudhary et al, 2012;Rikimaru et al, 2012); however, the aims of this research area could similarly be applied to the development of a drug geared towards the prevention and treatment of pre-clampsia and other adverse pregnancy outcomes, such as in the treatment of neonatal hyperoxia-induced lung injury for which rosiglitazone may serve a protective role (Cai and Xu, 2012). As yet, it is unknown whether PPAR-g agonists are toxic to the embryo and/or possess teratogenic effects; thus, caution must be exercised in the extrapolation of any data from experimental models to the clinical situation.…”

Section: Resultsmentioning

confidence: 99%

PPAR‐γ – a possible drug target for complicated pregnancies

McCarthy

Delany

Kenny

et al. 2013

British J Pharmacology

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Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors expressed in trophoblasts, which regulate both cell differentiation and proliferation. In recent years, evidence has linked PPARs to playing an integral role in pregnancy; specifically, PPAR-b and PPAR-g have been shown to play an integral role in placentation, with PPAR-g additionally serving to regulate trophoblast differentiation. Recent evidence has shown that PPAR-g expression is altered in many complications of pregnancy such as intrauterine growth restriction (IUGR), preterm birth, pre-clampsia and gestational diabetes. Thus, at present, accumulating evidence from the literature suggests both a pivotal role for PPAR-g in the progression of a healthy pregnancy and the possibility that PPAR-g may act as a therapeutic target in complicated pregnancies. This review aims to provide a succinct and comprehensive assessment of the role of PPAR-g in normal pregnancy and pregnancy complications, and finally its potential as a therapeutic target in the treatment and/or prevention of adverse pregnancy outcomes. AbbreviationsET-1, endothelin-1; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IKK, IkB kinase; RXR, retinoid X receptor; SO, superoxide; TXA2, thromboxane A2; VCAM-1, vascular adhesion molecule-1

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Section: Resultsmentioning

confidence: 99%

PPAR‐γ – a possible drug target for complicated pregnancies

McCarthy

Delany

Kenny

et al. 2013

British J Pharmacology

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“…10 Similarly, more selective drugs targeting PPAR γ and Scd1 promising fewer side effects are being pursued. 22, 38 Future studies must be able to link changes in systemic metabolism to local metabolic changes in prostate, which mandates a deeper understanding of the fundamental metabolic infrastructure regulating prostatic differentiation and what allostatic changes may occur in response to systemic metabolic stress. The data presented here suggest that a microenvironment of PPAR γ 2-mediated fatty acid metabolism by stroma or adipose may drive prostatic epithelial differentiation; however, under conditions of diabetes and obesity fatty acid supply may become saturated, leading to inflammation and hyperplasia in prostate disease (Figure 6f).…”

Section: Discussionmentioning

confidence: 99%

PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation

et al. 2012

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Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARγ isoforms in PPARγ knockout prostate epithelial cells. Expression and activation of either PPARγ 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. Differential effects of PPARγ isoforms included decreased basal cell differentiation, Scd1 expression and triglyceride fatty acid desaturation and increased tumorigenicity by PPARγ1. In contrast, PPARγ2 expression significantly increased basal cell differentiation, Scd1 expression and AR expression and responsiveness. Finally, in confirmation of in vitro data, a PPARγ agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARγ agonization increased prostatic differentiation markers, whereas HFD downregulated PPARγ-regulated genes and decreased prostate differentiation. These data provide a rationale for pursuing a fundamental metabolic understanding of changes to glucose and fatty acid metabolism in benign and malignant prostatic diseases associated with systemic metabolic stress.

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“…Molecular docking studies were performed by using Glide v5.6 (Schrodinger, LLC) [ 18 ]. The X-ray crystal of peroxisome proliferator-activated receptor gamma (PPARgamma) in complex with rosiglitazone (PDB entry code 1FM6) [ 19 ] was obtained from the RCSB Protein Data Bank (PDB) and utilized in order to get the detailed insights of ligand-protein structure in this study.…”

Section: Experimental Methodsmentioning

confidence: 99%

Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

Datar¹,

Jadhav²

2015

International Journal of Medicinal Chemistry

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Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series.

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A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: Design and synthesis of benzylpyrazole acylsulfonamides

Cited by 39 publications

References 33 publications

PPAR‐γ – a possible drug target for complicated pregnancies

PPAR‐γ – a possible drug target for complicated pregnancies

PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation

Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

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