Discovery of novel spiro[chromane-2,4′-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists

Koshizawa, Tomoaki; Morimoto, Toshiharu; Watanabe, Gen; Fukuda, Takayuki; Yamasaki, Nao; Hagita, Sumihiko; Sawada, Yuko; Okuda, Ayumu; Shibuya, Kimiyuki; Ohgiya, Tadaaki

doi:10.1016/j.bmcl.2018.08.010

Cited by 9 publications

(5 citation statements)

References 31 publications

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“…A number of publications have reported the discovery of piperidine transporters [46][47][48][49], voltage-gated potassium, calcium, sodium ion channels [50][51][52] and membrane [53][54][55] and G-protein-coupled receptors [56,57] as targets, which is also consistent with the SwissTargetPrediction data in this investigation. Accordingly, the probable effect on target classes in our case may cause the presence of both peripheral antiarrhythmic and local anaesthetic effects, and central effects such as anticonvulsant and antidepressant [58].…”

Section: Discussionsupporting

confidence: 89%

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Khaiitova

2023

J CLIN MED KAZ

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Background: The unique ability of piperidine to combine with various molecular fragments makes it possible to use its chemical structure to create new drugs with potential pharmacological effects. However, preliminary studies are required to predict the activity of new compounds in order to determine the direction of further preclinical studies. Aim: This study aims at determining the potential targets and spectrum of biological activity of new piperidine derivatives by the in silico method. Material and methods: Prediction of the effects on targets and the spectrum of biological activity of three new piperidine derivatives synthesized at the Bekturov Institute of Chemical Sciences JSC was analyzed in this study. The chemical structures of these compounds were studied in silico using the web tool SwissTargetPrediction to identify the most likely protein targets. PASS (Prediction of Activity Spectra for Substances) online tool was used to predict the possible pharmacological activity of the studied compounds. Results: New modified piperidine derivatives are able to affect different enzymes, receptors, transport systems, voltage-gated ion channels, thereby providing a wide range of biological activities applicable in various fields of medicine. These substances represent interest in the treatment of cancer, central nervous system diseases, as local anesthetic, antiarrhythmic and antimicrobial agents, and are promising for pharmacological activity demonstration in preclinical studies. Conclusion: A comprehensive analysis of the above results leads to the conclusion that the compounds under study should be considered as potential substances for the design of new highly effective medicinal agents with a wide range of practical applications.

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Section: Discussionsupporting

confidence: 89%

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Khaiitova

2023

J CLIN MED KAZ

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“…Compounds bearing an HFIP carbamate were found to be effective covalent inhibitors of monoacylglycerol lipase (MAGL), a serine hydrolase that catalyzes the hydrolysis of endocannabinoid 2-arachidonoylglycerol to arachidonic acid and glycerol in the brain. − The selective inhibition of MAGL is an attractive target for the treatment of an array of diseases, including those associated with chronic pain, inflammation, cancer, and neurodegeneration. A spirochromane derivative with a HFIP carbamate was assessed as a G-protein coupled receptor 119 agonist, while an imidazobenzodiazepine compound containing an HFIP ester was investigated as an asthma therapeutic …”

Section: Introductionmentioning

confidence: 99%

HFIP in Organic Synthesis

et al. 2022

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1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C–H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

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“…4). It should be mentioned that 1-Boc-piperidine is used as a synthetic precursor of antagonists for 5-HT6 serotonin receptors [17] and for selective agonists of GPR119 [15, 16] that were patented as anti-obese agents (PATENT CN201910382406.3A). In fact, results from a clinical trial suggest that 2-oleoyl glycerol has a protective action against overweight by acting on GPR119, which in turn may induce satiety [4].…”

Section: Discussionmentioning

confidence: 99%

“…Besides, a control group received only food and water ad libitum. We found significant differences between treatments (F [3, 120] = 4.052, p = 0.009; η 2 = 3.2) and weeks (F [5,120] = 46.564, p < 0.001; η 2 = 60), but not interactions (F [15,120] = 0.504, p = 0.9324). Animals included in the binge-eating protocol from the vehicle group gained more weight than the control group (which received standard diet only) throughout the experiment (Cohen's d = 0.46, r = 0.22, these values represent a small effect size) whereas animals treated with both 1 µmol kg −1 of 1-Bocpiperidine and 10 µmol kg −1 of 1-Boc-piperidine were not different between them or with respect to vehicle or control groups (p > 0.05; Cohen's d = 0.41 and 0.40, r = 0.2 and 0.2, respectively [effect sizes were small]).…”

Section: Weight Growth Curvementioning

confidence: 94%

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1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats

et al. 2021

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Background: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. Objectives: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. Methods: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg−1), or (iii) 1-Boc-piperidine (10 µmol kg−1). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. Results and Conclusions: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.

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Discovery of novel spiro[chromane-2,4′-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists

Cited by 9 publications

References 31 publications

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

HFIP in Organic Synthesis

1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats

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