Design, synthesis, and evaluation of novel aryl-tetrahydropyridine PPARα/γ dual agonists

Kim, Eunkyung; Park, Chan Sun; Han, Taedong; Bae, Myung-Ho; Chong, Wonee; Lee, Choong Hyun; Shin, Young Ah; Ahn, Byung-Nak; Kim, Mi Kyung; Shin, Chang Yell; Son, Miwon; Kim, Jin Kwan; Moon, Ho Sang; Shim, Hongjin; Kim, Eun Jung; Kim, Soon Hoe; Lim, Jong In; Lee, Chun Ho

doi:10.1016/j.bmcl.2008.08.020

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…Methanolysis of the resulting products gave 24 and 25. A Boc-protected piperidine was installed via Suzuki reaction of 26 and 27, 18 followed by hydrogenation to give 28 in 42% yield over two steps (Scheme 7). 6-Chloropyridazine 29 19 and 5-bromo-pyrazine 30 20 were subjected to palladium-catalyzed cross-coupling with benzophenone imine, an ammonia synthon, 21 and subsequently deprotected to yield 31 and 32 (Scheme 8).…”

Section: Chemistrymentioning

confidence: 99%

4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

Cho¹,

Borland²,

Brain³

et al. 2010

J. Med. Chem.

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Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.

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Section: Chemistrymentioning

confidence: 99%

4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

Cho¹,

Borland²,

Brain³

et al. 2010

J. Med. Chem.

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“…A major source of ECM formation in HSC processing is myofibroblastic transition [ 16 , 17 ]. Myofibroblastic (MFB) differentiation and matrix accumulation of HSC are usually induced by profibrogenic mediators like TGF- β and the β -isoform of platelet-derived growth factor (PDGF) [ 16 – 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Activated HSCs promote not only the synthesis and deposition of the ECM component but also the induction of α -SMA. And these signaling cascades accelerate the growth of activated HSCs and contribute to the development of hepatic fibrosis [ 20 ]. Therefore, HSC play a key role during fibrosis in response to TGF- β through increased synthesis of ECM proteins, especially collagen-I and-II [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…First of all, removing the relevant cause of chronic liver disease is the most effective way to prevent fibrosis. Examples include elimination of excess iron or copper in genetic hemochromatosis or Wilson's disease, abstinence from alcohol, anthelminthic therapy in schistosomiasis, clearance of HBV or HCV in chronic viral hepatitis, and biliary decompression in bile duct obstruction [ 20 , 23 – 26 ]. Anti-inflammatory medications may be beneficial in treating fibrosis, because inflammatory mediators may stimulate HSC activation in chronic liver diseases such as viral or autoimmune hepatitis and drug-induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

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Effects of β-sitosterol derived from Artemisia capillaris on the activated human hepatic stellate cells and dimethylnitrosamine-induced mouse liver fibrosis

Kim

Yang

Lee

et al. 2014

BMC Complement Altern Med

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Backgroundβ-sitosterol is a cholesterol-like phytosterol, which widely distributed in the plant kingdom. Here, anti-fibrotic effect of the β-sitosterol was studied using the activated human hepatic stellate cell (HSC) model and dimethylnitrosamine (DMN)-induced mouse hepatic fibrosis model.MethodHSCs were activated by transforming growth factor-β (TGF-β) and the collagen-1 and α-smooth muscle actin (α-SMA) expressions were measured at the mRNA and protein level. We also studied the effect β-sitosterol using DMN-induced mouse hepatic fibrosis model. We then measured the collagen-1 and α-SMA expression levels in vivo to investigate anti-hepatofibrotic effect of β-sitosterol, at both of the mRNA and protein level.Resultsβ-sitosterol down regulated the mRNA and protein expression levels of collagen-1 and α-SMA in activated HSC. Oral administration of the β-sitosterol successfully alleviated the DMN-induced mouse liver damage and prevented collagen accumulation. The mRNA and protein expression levels of collagen-1 and α-SMA were also down regulated in β-sitosterol treated mouse group.ConclusionsThis study shows the effect of β-sitosterol on the TGF-β -or DMN-induced hepatofibrosis. Hence, we demonstrate the β-sitosterol as a potential therapeutic agent for the hepatofibrosis.

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“…1), is a well-balanced PPARα/γ dual agonist which is newly synthesized by Dong-A Research Center and Yuhan Research Institute (Kim et al, 2008a). PAR-5359 has the excellent antihyperglycemic and hypolipidemic activities in vitro and in vivo (Kim et al, 2008a, b).…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatography-tandem mass spectrometry of a new PPARα/γ dual agonist PAR-5359 in rat plasma

et al. 2009

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PAR-5359, 3-(4-{2-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy}-phenyl)-2-ethoxypropionic acid, is a well-balanced PPARalpha/gamma dual agonist with the excellent antihyperglycemic and hypolipidemic activities. A reliable, selective and sensitive high-performance liquid chromatography with electrospray ionization tandem mass spectrometry was developed for the determination of PAR-5359 in rat plasma. PAR-5359 was twice extracted from rat plasma using methyl tert-butyl ether at neutral pH. The analytes were separated on an Allure Biphenyl column with the mobile phase of 78% methanol in 10 mM ammonium formate (pH 3.0) and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r = 0.9993) over the concentration range of 2.00-1000.0 ng/mL and the lower limit of quantification was 2.00 ng/mL using 50 microL plasma sample. The coefficient of variation and relative error at four QC levels were 1.2 to 12.3% and -2.5 to 6.3%, respectively. The present method was successfully applied to the pharmacokinetic study of PAR-5359 after oral dose of PAR-5359 at a dose of 1 mg/kg to male SD rats.

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Design, synthesis, and evaluation of novel aryl-tetrahydropyridine PPARα/γ dual agonists

Cited by 7 publications

References 15 publications

4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

Effects of β-sitosterol derived from Artemisia capillaris on the activated human hepatic stellate cells and dimethylnitrosamine-induced mouse liver fibrosis

Liquid chromatography-tandem mass spectrometry of a new PPARα/γ dual agonist PAR-5359 in rat plasma

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