Discovery of 1‐(2,4‐Dichlorophenyl)‐4‐ethyl‐5‐(5‐(2‐(4‐(trifluoromethyl)phenyl)ethynyl)thiophen‐2‐yl)‐<i>N</i>‐(piperidin‐1‐yl)‐1<i>H</i>‐pyrazole‐3‐carboxamide as a Potential Peripheral Cannabinoid‐1 Receptor Inverse Agonist

Hung, Ming‐Shiu; Chang, C. P.; Li, Ting-Chieh; Yeh, Teng‐Kuang; Song, Jen‐Shin; Lin, Ying‐Ting; Wu, Chien-Huang; Kuo, Po-Chu; Amancha, Prashanth K.; Wong, Ying‐Chieh; Hsiao, Wen-Chi; Chao, Yu‐Sheng; Shia, Kak‐Shan

doi:10.1002/cmdc.201000246

Cited by 24 publications

(26 citation statements)

References 20 publications

(17 reference statements)

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“…18 BPR697 is a peripherally restricted CB1 inverse agonist, as shown by its inability to attenuate cannabinoid agonist-induced responses as well as its low brain penetration. 21 Here, administration of BPR697 did not influence food intake, either in an acute condition fed with standard chow diet or in a chronic condition with high-fat diet. This result supports the essential role of the central CB1 receptor in the regulation of food intake.…”

Section: Discussionmentioning

confidence: 63%

“…This disparity in pharmacokinetic properties may lead to different brain penetration affecting the outcome of a simple comparison. Furthermore, the in vitro activity of BPR697 is less potent than rimonabant, 21 a compound with similar in vitro profile to AM6545, 29 which might reduce its potency in vivo. This discordance suggests that whether peripheral CB1 receptors modulate food intake remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…21 It exhibits a low brain to plasma concentration ratio (B/P ¼ 1/23) relative to a counterpart, rimonabant, with much higher central activity (B/P ¼ 3/1). 21 Therefore, BPR697 was used here to examine the efficacy of peripheral CB1 antagonism on whole-body energy expenditure and post-absorptive state metabolic alteration in addition to body weight and food intake changes. …”

Section: Introductionmentioning

confidence: 99%

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Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Lin

Shia

et al. 2011

Int J Obes

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OBJECTIVE: Fatty acid oxidation has been implicated in amelioration of obesity by burning off excessive accumulated lipid. BPR697, a peripheral cannabinoid receptor 1 (CB1) antagonist, elevated fat oxidation without added energy expenditure. Its impact on food intake, body weight changes and metabolic alterations were examined in rats fed standard chow and in diet-induced obesity (DIO) mice. MATERIALS AND METHODS: CB1 agonist-induced hypothermia and analgesia responses were measured to examine the brain activity of BPR697. The acute effects of BPR697 on food intake, body weight change and post-absorptive metabolic profiles were investigated in rats. Energy utilization with BPR697 was examined by indirect calorimetry. Chronic treatment of DIO mice was used to evaluate the long-term effects of BPR697. RESULTS: Distribution of BPR697 was significantly biased in favor of the periphery instead of the brain, as shown by its low brain/plasma concentration ratio and confirmed by the negative response of BPR697 in CB1 agonist-induced hypothermia and analgesia. When administered to rats at 20 mg kg À1 , BPR697 showed a unique spectrum of effects with significant weight loss without altered food intake. Furthermore, BPR697 increased serum levels of free fatty acids and ketone bodies and reduced hepatic lipid accumulation with preservation of liver glycogen in postprandial rats. Indirect calorimetric profiling of BPR697 revealed a similar trend, shifting whole-body energy catabolism toward fat oxidation, but without elevated energy expenditure. In DIO mice with chronic treatment, animals treated with BPR697 at 20 mg kg À1 resisted weight gain and showed a reduction of high-fat-induced cardiometabolic abnormalities such as hyperglycemia, abdominal fat and liver steatosis. CONCLUSION: The induction of fatty acid oxidation without concomitant elevation of energy expenditure by the peripheral CB1 antagonist BPR697 is sufficient to cause substantial weight loss in chow-fed rats. In the presence of high-dietary fat intake, BPR697 resists weight gain and alleviates obesity-related cardiometabolic risk factors. Keywords: fatty acid oxidation; peripheral CB1 antagonist; food intake; body weight; cardiometabolic risk factors INTRODUCTION Energy homeostasis, the balance between energy intake and energy expenditure, is regulated by coordinated interaction between the central nervous system and peripheral tissues. Elucidation of the metabolic factors influencing energy balance, and lipid and glucose metabolism has been a major focus of research interest, and many studies of the underlying mechanisms have revealed the importance of communication between the central nervous system and the periphery. 1--3 Among various factors involved in energy balance, endocannabinoids (for example, anandamide and 2-arachidonoylglycerol) mediate a positive energy balance via activation of their receptor, cannabinoid receptor 1 (CB1). The brain CB1 receptor, a G proteincoupled receptor, is present at a high level in brain tissue, and enhances appetite a...

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Lin

Shia

et al. 2011

Int J Obes

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“…These compounds exhibited CB1 receptor antagonistic activity equal to or less than 10 µM. (147)(148)(149) Maitra et al [126] invented novel peripherally restricted diphenyl purine derivatives that did not cross the BBB and thus minimized CNS-related side effects. Compound (150) exhibited a K i value of 0.355 µM with CB1/CB2 ratio of 30.2.…”

Section: Purine Derivativesmentioning

confidence: 99%

“…Further development of compounds of this class may be beneficial for the pharmacotherapy of this metabolic disorder. Another company 7TM Pharma [147] has also identified compound TM38837 [148], a second-generation CB1 receptor antagonist that acts peripherally [149] and has the potential to treat several metabolic disorders without CNS side effects. In 2010, the company announced that they have successfully conducted and completed Phase I clinical trials of compound TM38837 for the treatment of obesity and related metabolic disorders [147] and this type of compound should be further developed.…”

Section: Expert Opinionmentioning

confidence: 99%

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents

Sharma

Murumkar

Barmade

et al. 2015

Expert Opinion on Therapeutic Patents

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Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity

et al. 2015

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Peripherally acting cannabinoid 1 (CB1) receptor antagonists are considered as potential therapeutics for the treatment of obesity with desired efficacy and reduced central nervous system side effects. A dataset of 72 compounds containing the 1,5-diaryl pyrazole basic skeleton having peripheral CB1 receptor antagonistic activity was utilized for three-dimensional quantitative structure-activity relationship studies. Compounds of the series exhibited high variations in the biological activity and chemical structures. Different types of molecular alignments, such as atom-based, data-based, centroid-based and centroid/atom-based were utilized to develop the best CoMFA model. The best CoMFA model was obtained with a database alignment and the same alignment was further used for the development of a CoMSIA model. The best developed CoMFA model had [Formula: see text] with six components, [Formula: see text] while the best developed CoMSIA model had [Formula: see text] with six components, [Formula: see text] and [Formula: see text] The predictive [Formula: see text] values of these two models showed test set predictions of 0.528 and 0.679 for the best CoMFA and CoMSIA models, respectively. Based on a higher [Formula: see text] value, the CoMSIA model was found to be the best one. The prediction accuracy and reliability of the best developed CoMSIA model have been validated using well-established methods. Using the inputs from the best CoMSIA contour maps, several novel highly selective peripherally acting CB1 receptor antagonists have been designed and reported herein.

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Discovery of 1‐(2,4‐Dichlorophenyl)‐4‐ethyl‐5‐(5‐(2‐(4‐(trifluoromethyl)phenyl)ethynyl)thiophen‐2‐yl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide as a Potential Peripheral Cannabinoid‐1 Receptor Inverse Agonist

Cited by 24 publications

References 20 publications

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents

Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity

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