One-pot synthesis of novel tert-butyl-4-substituted phenyl-1H-1,2,3-triazolo piperazine/piperidine carboxylates, potential GPR119 agonists

Bashetti, Nagaraju; Kumar, J. Vinoth; Seelam, Nareshvarma; Prasanna, B.; Mintz, Akiva; Damuka, Naresh; Devanathan, Sriram; Sai, Kiran Kumar Solingapuram

doi:10.1016/j.bmcl.2019.126707

Cited by 3 publications

(6 citation statements)

References 20 publications

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“…We recently reported a novel, one-pot method for synthesizing oxadiazole-substituted piperidine analogues using copper iodide/diisopropylethylamine-assisted click chemistry 23 and their in vitro selectivity for GPR119 binding. The discovery of several synthetic small-molecule GPR119 agonists has aided the receptor role in metabolic homeostasis and the applications of agonistic molecules as drugs against T2DM and obesity.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…N-Boc group deprotection was performed under acidic conditions to achieve oxadiazole building block 3 in 65% yield. This intermediate 3 was then reacted with 4,6dichloro-5-nitropyrimidine 4 to give piperidine substituted 23 used the basic luciferase activation-based reporter expression assay to study the efficacy of our newly synthesized oxadiazolesubstituted piperidine analogues in GPR119 expressing HEK-293 cells (GPR119/pCRE-luc). Here, we evaluated the GPR119 binding potential of KSS3 and KSS4 using the routinely used commercial Tango GPCR assay system.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Some of the salient features of AR231453 include no off-target activity, high insulin secretion in a glucose-dependent manner, significant enhancement of cAMP accumulation, and GLP-1 release with no side effects in multiple animal models of T2DM and obesity. We used AR231453, a potent GPR119 agonist, ,− as a lead to design our novel derivatives. Based on the structure–activity relationship (SAR) from the key skeleton of AR231453, we retained the pharmacophore (isopropyl oxadiazole side chain) and incorporated [ 18 F]-amenable groups at the phenyl end of the core .…”

Section: Resultsmentioning

confidence: 99%

“…As depicted in Scheme 1, KSS3, KSS4, and their corresponding tosyl precursors were synthesized following previously published methods with slight modifications. 27−29 Briefly, the starting material with carboxylic acid 1 was reacted with hydroxylamine to provide the 1,2,-oxadiazole intermediate 23 used the basic luciferase activation-based reporter expression assay to study the efficacy of our newly synthesized oxadiazolesubstituted piperidine analogues in GPR119 expressing HEK-293 cells (GPR119/pCRE-luc). Here, we evaluated the GPR119 binding potential of KSS3 and KSS4 using the routinely used commercial Tango GPCR assay system.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Developed by Arena Pharmaceuticals, AR231453 is a well-characterized and potent small-molecule GPR119 agonist with an affinity of 5.5 nM. ,− Its oral administration significantly improved circulating levels of insulin and lowered blood glucose concentrations in animal models of T2DM. ,,, We synthesized two oxadiazole derivatives, KSS3 and KSS4, using AR231453 as the lead structure because of its high target autoradiography specificity and safety profile. In this study, we reported the synthesis, radiochemistry, and initial biological evaluations in vitro , in vivo , and ex vivo of two high-affinity oxadiazole-based GRP119 PET radiotracers [ 18 F]KSS3 and [ 18 F]KSS4 in rodents for the first time.…”

Section: Introductionmentioning

confidence: 99%

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First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

Bansode,

Damuka,

Bashetti

et al. 2023

J. Med. Chem.

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G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3’s high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3’s high specificity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

Bansode,

Damuka,

Bashetti

et al. 2023

J. Med. Chem.

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GPR119 agonists: Novel therapeutic agents for type 2 diabetes mellitus

Manaithiya

Alam

Sharma

et al. 2021

Bioorganic Chemistry

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Role of the G protein-coupled receptors GPR84 and GPR119 in the central regulation of food intake in rainbow trout

Velasco

Conde-Sieira

Comesaña

et al. 2021

Journal of Experimental Biology

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We evaluated the role of GPR84 and GPR119 in food intake regulation in fish using rainbow trout (Oncorhynchus mykiss) as a model. In a first experiment, we assessed the effects on food intake of intracerebroventricular treatment with agonists of these receptors. In a second experiment, we assessed in hypothalamus and hindbrain the impact of the same treatments on mRNA abundance of neuropeptides involved in the metabolic control of food intake (npy, agrp1, pomca1, and cartpt) as well as in changes in parameters related to signalling pathways and transcription factors involved in the integrative response leading to neuropeptide production. Treatment with both agonists elicited an anorectic response in rainbow trout attributable to changes observed in the mRNA abundance of the four neuropeptides. Changes in neuropeptides relate to changes observed in mRNA abundance and phosphorylation status of the transcription factor Foxo1. These changes occurred in parallel with changes in phosphorylation status of Ampkα and Akt, mRNA abundance of mTOR as well as in signalling pathways related to PLCβ and IP3. These results allow us to suggest that 1) at least part of the capacity of fish brain to sense MCFA like octanoate depends on the function of GPR84, and 2) the capacity of fish brain to sense NAE or triglyceride-derived molecules through binding of these ligands to GPR119.

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One-pot synthesis of novel tert-butyl-4-substituted phenyl-1H-1,2,3-triazolo piperazine/piperidine carboxylates, potential GPR119 agonists

Cited by 3 publications

References 20 publications

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

GPR119 agonists: Novel therapeutic agents for type 2 diabetes mellitus

Role of the G protein-coupled receptors GPR84 and GPR119 in the central regulation of food intake in rainbow trout

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