Derivatives of 1,4-bis(3-hydroxycarbonyl-4-hydroxyl)styrylbenzene as PTP1B inhibitors with hypoglycemic activity

Shrestha, Suja; Bhattarai, Bharat Raj; Kafle, Bhooshan; Lee, Keun‐Hyeung; Cho, Hyeongjin

doi:10.1016/j.bmc.2008.07.090

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…Commercially available boronic acid 9 and bromoaldehyde 10 were coupled under Suzuki conditions [46,47] affording the biaryl intermediate ( 11 ). A nitro-aldol reaction [48,49] on 11 followed by reduction of the nitrostyrene ( 12 ), gave amine 13 .…”

Section: Resultsmentioning

confidence: 99%

Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

Pecic

McAnuff

Harding

2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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Nantenine, as well as a number of flexible analogs, were evaluated for acetylcholinesterase (AChE) inhibitory activity in microplate spectrophotometric assays based on Ellman’s method. It was found that the rigid aporphine core of nantenine is an important structural requirement for its anticholinesterase activity. Nantenine showed mixed inhibition kinetics in enzyme assays. Molecular docking experiments suggest that nantenine binds preferentially to the catalytic site of AChE but is also capable of interacting with the peripheral anionic site (PAS) of the enzyme, thus accounting for its mixed inhibition profile. The aporphine core of nantenine may thus be a useful template for the design of novel PAS or dual-site AChE inhibitors. Inhibiting the PAS is desirable for prevention of aggregation of the amyloid peptide Aβ, a major causative factor in the progression of Alzheimer’s disease (AD).

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Section: Resultsmentioning

confidence: 99%

Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

Pecic

McAnuff

Harding

2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…[15] TC-PTP was purchased from New England Biolabs, (Beverly, USA). Chemical shifts are reported in units of parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (CHCl 3 : d = 7.26 ppm for 1 H, CDCl 3 : d = 77.0 ppm for 13 C NMR spectra).…”

Section: Methodsmentioning

confidence: 99%

Isoxazol‐5(4H)one Derivatives as PTP1B Inhibitors Showing an Anti‐Obesity Effect

Kafle

Aher

Khadka

et al. 2011

Chemistry An Asian Journal

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In developing inhibitors of therapeutic target enzymes, significant time and effort are committed to the preparation of large numbers of compounds. In an effort to develop a potent inhibitor of protein tyrosine phosphatase (PTP) 1B as an anti-obesity and/or anti-diabetic agent, we constructed an isoxazolone chemical library by using a simplified procedure that circumvents tedious workup and purification steps. The 10×7 isoxazolone derivatives were synthesized by coupling the two halves of the target compounds. When mixed and heated in test tubes, the precursors produced the reaction products as precipitates. After brief washing, the products were pure enough to be used for enzymatic experiments. With the precursors for the coupling reactions prepared, the 10×7 library compounds could be prepared in a day by using the present protocol. The library compounds thus obtained were examined for their inhibitory activities against PTP1B. Among them, compound C3 was the most potent inhibitor of PTP1B with an IC(50) of 2.3 μM. The in vivo effect of C3 was also examined in an obesity-prone mouse strain. Diet-induced obese (DIO)/diabetic mice were divided into two groups and each group was fed a high-fat diet (HFD) or HFD+C3 for four weeks. The group of C3-fed mice gained significantly less weight relative to the HFD-fed control group during the four weeks of the drug feeding period. In contrast to the anti-obesity effect of C3, no difference was observed in the glycemic control of the HFD and HFD+C3 mice groups.

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“…As salicylic acid has been reported as a novel and cell permeable p-Tyr mimetic, 63 Cho synthesized a series of salicylic acid derivatives as PTP1B inhibitors, and found compounds 23, 24, 25, 26, and 27 had IC 50 or K i values at sub mM range against PTP1B with 4-to 14-fold specificities over Tc-PTP. [76][77][78][79] The significance of these compounds was that they showed good oral bioavailability and were able to suppress high-fat-diet induced weight gain and adipocyte fat storage in mouse models. Interestingly, compounds 23 and 26 were also reported to be potent inhibitors of kinase IKK-b, indicating their in vivo targets may not be limited to PTP1B.…”

Section: Carboxylic Acidsmentioning

confidence: 99%

Chapter 6. Recent Advances in PTP1B Inhibitor Development for the Treatment of Type 2 Diabetes and Obesity

He¹,

Zeng²,

He³

et al. 2012

Drug Discovery

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Derivatives of 1,4-bis(3-hydroxycarbonyl-4-hydroxyl)styrylbenzene as PTP1B inhibitors with hypoglycemic activity

Cited by 14 publications

References 31 publications

Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

Isoxazol‐5(4H)one Derivatives as PTP1B Inhibitors Showing an Anti‐Obesity Effect

Chapter 6. Recent Advances in PTP1B Inhibitor Development for the Treatment of Type 2 Diabetes and Obesity

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