Discovery of 1-(2,4-Dichlorophenyl)-<i>N</i>-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1<i>H</i>-pyrazole-3-carboxamide as a Novel Peripherally Restricted Cannabinoid-1 Receptor Antagonist with Significant Weight-Loss Efficacy in Diet-Induced Obese Mice

Chang, C. P.; Wu, Chien-Huang; Song, Jen‐Shin; Chou, Ming‐Chen; Wong, Ying‐Chieh; Lin, Ying‐Ting; Yeh, Teng‐Kuang; Sadani, Amit A.; Ou, Ming-Hung; Chen, Kun-Hung; Chen, Pei-Hsuan; Kuo, Po-Chu; Tseng, Chen‐Tso; Chang, Kuei-Hua; Tseng, Shi-Liang; Chao, Yu‐Sheng; Hung, Ming‐Shiu; Shia, Kak‐Shan

doi:10.1021/jm401158e

Cited by 33 publications

(20 citation statements)

References 49 publications

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“…In a previous study, Tam et al reported that the absence of the neurobehavioral effects of AM6545 and JD5037, novel peripherally-restricted CB1R antagonists, were similar to those observed with rimonabant, but indicated that few neuropsychiatric side-effects occurred in humans (28,29). Additionally, 1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl) phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide, another potential peripherally restricted CB1R antagonist, was discovered by Taiwanese investigators and demonstrated a significant weight-loss efficacy in mice with DIO (56).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Chen¹,

Lee

Kwok

et al. 2016

International Journal of Molecular Medicine

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Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA‑IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.

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Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Chen¹,

Lee

Kwok

et al. 2016

International Journal of Molecular Medicine

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“…34) was found to be most potent cannabinoid-1 receptor antagonist with K i values of 0.3 nM (hCB1R), 21.0 nM (hCB2R) and EC 50 of 3 nM (CB1R). Compound 297 is currently under development for treating obesity and the related metabolic syndrome [219].…”

Section: Cannabinoid Receptor Agonistsmentioning

confidence: 99%

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review

Zhao

Rakesh

Ravidar

et al. 2019

European Journal of Medicinal Chemistry

403

183

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a b s t r a c tSulfur (S VI ) based moieties, especially, the sulfonyl or sulfonamide based analogues have showed a variety of pharmacological properties, and its derivatives propose a high degree of structural diversity that has established useful for the finding of new therapeutic agents. The developments of new less toxic, low cost and highly active sulfonamides containing analogues are hot research topics in medicinal chemistry. Currently, more than 150 FDA approved Sulfur (S VI )-based drugs are available in the market, and they are widely used to treat various types of diseases with therapeutic power. This comprehensive review highlights the recent developments of sulfonyl or sulfonamides based compounds in huge range of therapeutic applications such as antimicrobial, anti-inflammatory, antiviral, anticonvulsant, antitubercular, antidiabetic, antileishmanial, carbonic anhydrase, antimalarial, anticancer and other medicinal agents. We believe that, this review article is useful to inspire new ideas for structural design and developments of less toxic and powerful Sulfur (S VI ) based drugs against the numerous death-causing diseases.

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“…Currently, the availability of peripheral CB1R antagonists is limited , and most were designed based on the templates of centrally acting CB1R antagonists such as rimonabant and SLV‐319. The CB1R antagonist TM38837 (7TM Pharma, Denmark) is the most advanced of these peripherally acting compounds, having completed a phase I clinical trial .…”

Section: Introductionmentioning

confidence: 99%

A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis

Hsiao

Shia

Wang

et al. 2015

Diabetes Obesity Metabolism

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BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

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Cited by 33 publications

References 49 publications

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review

A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis

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