Synthesis and biological evaluation of 1, 2, 4‐oxadiazole derivatives as novel GPR119 agonists

Fu, Suhong; Xiang, Wei; Chen, Jinying; Ma, Liang; Chen, Lijuan

doi:10.1111/cbdd.12890

Cited by 6 publications

(2 citation statements)

References 21 publications

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“…The S-M reactionh as already been reported under some limited rangeso ff low conditions, [7,11] nonetheless, we explored its utility towardt he synthesis of important synthons [12] in am icrofluidic reactor using EtOH as solvent to broadly explore the utility of this transformation. [7, 10c] Automated HTE of S-M reactions was performed in 96-well plates using 4-hydroxyphenylboronic acid and 11 different aryl halides( Scheme 1) with order of addition, stoichiometry,t emperature, and concentration as independentv ariables.…”

Section: Introductionmentioning

confidence: 99%

High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross‐Coupling Reactions

Jaman

Mufti

Sah

et al. 2018

Chemistry A European J

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Traditional methods to discover optimal reaction conditions for small molecule synthesis is a time-consuming effort that requires large quantities of material and a significant expenditure of labor. High-throughput techniques are a potentially transformative approach for reaction condition screening, however, rapid validation of the reaction hotspots under continuous flow conditions remains necessary to build confidence in high throughput screening hits. Continuous flow technology offers the opportunity to upscale the screening hotspots and optimize their output of the target compounds due to the exceptional heat and mass transfer ability of flow reactions that are conducted in a smaller and safer reaction volume. We report a robotic high throughput technique to execute reactions in multi-well plates that were coupled with fast mass spectrometric analysis using an autosampler to accelerate the reaction screening process. Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions were screened in this system and a heat map was generated to identify the best reaction conditions for downstream scale-up under continuous flow. Here, high throughput experimentation reactions in 96-well plates were performed for 1 h at 50 °C, 100 °C, 150 °C, and 200 °C before diluting them into 384-well plates for mass analysis. With the aid of high throughput tools, 648 unique experiments were conducted in duplicate. The cross-coupling reactions were evaluated as a function of stoichiometry, temperature, concentration, order of addition, and substrate type. The hotspots from high throughput experimentation were examined using a microfluidic Chemtrix system that confirmed the positive reaction leads as true positives. Negative outcomes identified by these experiments were found to be true negatives by microfluidic reaction evaluation. Quantitation of product yields was performed using high-performance liquid chromatography-mass spectrometry (HPLC/MS-MS).

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Section: Introductionmentioning

confidence: 99%

High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross‐Coupling Reactions

Jaman

Mufti

Sah

et al. 2018

Chemistry A European J

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“…For example, AR231453 from Arena Pharmaceuticals and PSN632408 from Prosidion Ltd were two of the earlier potent and orally efficacious GPR119 agonists with significant published preclinical data. However, owing to the loss of efficacy as well as indicate tachyphylaxis, the positive results obtained in preclinical studies did not appear in the phase II clinical trials, which brought uncertainty to the clinical prospects of GPR119 agonists for the treatment of T2DM . Following the initial enthusiasm, more and more novel GPR119 agonists with diverse chemical structures have been patented and reported, some of which were also under clinical trials, as shown in Figure .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of 2‐(4‐(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists

Zhou

Zhu²,

Zhang

et al. 2018

Chem Biol Drug Des

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This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high-fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development.

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1,2,4-Oxadiazoles

Piccionello

Pibiri

Pace

et al. 2022

Comprehensive Heterocyclic Chemistry IV

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Synthesis and biological evaluation of 1, 2, 4‐oxadiazole derivatives as novel GPR119 agonists

Cited by 6 publications

References 21 publications

High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross‐Coupling Reactions

High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross‐Coupling Reactions

Design, synthesis, and biological evaluation of 2‐(4‐(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists

1,2,4-Oxadiazoles

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