Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A review

Haider, Kashif; Pathak, Ankita; Rohilla, A.; Haider, Rafi; Ahmad, Kamal; Yar, Mohammad Shahar

doi:10.1016/j.ejmech.2019.111773

Cited by 29 publications

(22 citation statements)

References 87 publications

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“…The main glucose transporters are SGLT1 and SGLT2. However, both do the same function, but they differ widely in properties [79,80]. Normally, blood glucose is accumulated to the side of glomerular membrane through tubular lumen.…”

Section: Resultsmentioning

confidence: 99%

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

et al. 2021

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The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

et al. 2021

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“…15 A) 323 . The in vitro assay indicated that ipragliflozin ( 32 ) demonstrated 254-fold selectivity for SGLT2 over SGLT1, with the IC 50 values of 7.4 and 1876 nmol/L, respectively 323 , 324 . It showed no significant effects on human SGLT4 or SGLT5 isoforms (IC 50 > 1.0 μmol/L) or GLUT at concentrations up to 3.0 μmol/L 325 .…”

Section: Carbohydrate-based Antidiabeticsmentioning

confidence: 99%

Carbohydrate-based drugs launched during 2000−2021

Cao

Jiao

et al. 2022

Acta Pharmaceutica Sinica B

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“…None of the O -glycoside SGLT2 inhibitors, such as T1095-A, sergliflozin-A, etc., have been developed as antidiabetic drugs because they are easily hydrolyzed by β-glucosidase-like phlorizin, even though 6-OH of their glucosyl moiety is modified with an ester group (T1095 and sergliflozin in Figure b). , Thus, many methods for the synthesis of C -glycosides have been developed, which were expected to improve the synthesis of these C -glycoside gliflozin drugs . However, the high cost of synthesizing C -glucoside gliflozins can hardly be reduced since the C–C coupling glycosylations require harsh conditions (ultra-low temperature and ultra-dry solvent) and lead to products with α/β-anomers that are difficult to purify (Figure a) . Thioglycosides, as mimetics of biologically active O -glycosides, have unique advantages in their resistance to hydrolysis under both acidic and enzymatic conditions. − Thus, thiosugar moieties have been found in natural products, enzyme inhibitors, drugs, and pharmaceutically active agents. − We speculated that the thioglucoside analogues of gliflozins (TAGs) should be resistant to hydrolysis by β-glucosidase and may be developed as new gliflozin drugs.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs

Feng,

Guo,

Tang

et al. 2023

J. Med. Chem.

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In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to Oglucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against β-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC 50 : 2.0−5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.

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Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A review

Cited by 29 publications

References 87 publications

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

Carbohydrate-based drugs launched during 2000−2021

Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs

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