C-aryl Glucoside Research Articles

Advances in SGLT2 Inhibitors for Type 2 Diabetes Management

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a significant class of medications for the management of type 2 diabetes mellitus, offering improved glycemic control and cardiovascular benefits. This review focuses on the development of various SGLT2 inhibitors, highlighting their chemical structures, pharmacological properties, and therapeutic potential. Methods: A comprehensive literature review was conducted, summarizing the synthesis and biological evaluation of multiple SGLT2 inhibitors, including novel compounds derived from C-aryl glucoside scaffolds, C-glucosides, and 5α-carba-β-D-glucopyranose derivatives. Studies utilized various techniques, such as click chemistry, Friedel-Crafts alkylation, and pharmacokinetic assessments, to evaluate the efficacy and selectivity of these inhibitors. Results: Several promising compounds were identified, including compound 1 (GCC5694A) with an IC50 of 0.460 nM against SGLT2 and strong selectivity for SGLT1, and compound 26, which exhibited an IC50 of 4.47 nM, surpassing dapagliflozin. Novel derivatives, such as compound 22 (IC50 = 47 nM) and compound 27, demonstrated significant inhibitory effects and selectivity profiles. Pharmacokinetic studies revealed compounds like compound 28 had enhanced half-lives compared to established drugs like sergliflozin. Additionally, compounds such as the nitric oxide-releasing dapagliflozin derivative exhibited dual anti-diabetic and anti-thrombotic properties. Conclusion: The ongoing development of SGLT2 inhibitors demonstrates substantial advancements in therapeutic options for type 2 diabetes. The structural modifications and novel compounds explored in this review highlight the potential for improved efficacy and safety profiles, suggesting that these new agents could play a vital role in diabetes management and warrant further clinical investigation.

Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes

Sodium-dependent glucose co-transporter 2 (SGLT2) has emerged as a promising drug target for the treatment of type 2 diabetes, and recently, several SGLT2 inhibitors have been approved for clinical use. A series of molecules with a C-aryl glucoside scaffold was designed and synthesized for biological evaluation. Among the molecules tested, a dihydrobenzofuran-containing analog, 14g (GCC5694A), exhibited excellentin vitro activity against SGLT2 (IC50 = 0.460 nM), good selectivity for SGLT1, and good metabolic stability. Data from further evaluation of the compound in animal models showed that this molecule is a promising candidate for development as an anti-diabetic agent.

Integrated computational approach on sodium-glucose co-transporter 2 (SGLT2) Inhibitors for the development of novel antidiabetic agents

Nowadays, diabetes mellitus has become a global health concern. Various marketed drugs are available to treat diabetes but many of them produced undesirable side effects. From past few decades, sodium dependent glucose co-transporter 2 (SGLT2) is regarded as a hot target for type 2 diabetes mellitus due to its novel mechanism of action with less side effects. A majority of computational studies have been performed by many researchers to find out novel inhibitors to the target SGLT2. In the present study, we performed computational analysis using different drug designing tools to ascertain the best possible molecules from a dataset of 90 C-aryl glucoside analogues obtained from literature. The pharmacophore mapping study was performed to determine the key functional features responsible for the activity. The 3D-QSAR (CoMFA, CoMSIA and atom based QSAR) analysis was carried out by using 63 molecules as a training set & rest of the 27 as test sets to know the contribution of different fields & atoms for model development. The MFA with PLS method was used to generate a statistically significant model (q2 = 0.7387, r2 = 0.8670). The QSAR model was validated using LOO cross-validation (r2CV = 0.5305) & external validation (r2pred = 0.985). The homology model of SGLT2 was constructed using co-crystallized structure (PDB: 2XQ2_A) as templates & validated by Ramachandran plot. The docking study of potent C-aryl glucoside analogues (22, 23 and 26) showed highest SP docking scores (-7.22, -7.012 & -6.867) with the involvement of critical interactions with amino acid residues Asn75, His80, Glu99, Ser287, Tyr290 & Trp291. ADME analysis provides valuable information about drugability of newly designed compounds. Correlating the docking results with the 3D-QSAR and binding free energy calculations by MMGBSA analysis can suggest the active conformation of SGLT2 inhibitors and the nature of interactive fields important for binding and activity.

Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans

Bexagliflozin is a C-aryl glucoside inhibitor of human sodium-glucose linked transporter 2 (SGLT2) that undergoes oxidation and glucuronidation to form six principal metabolites in humans.In vitro metabolism by human liver microsomes and recombinant enzymes is primarily mediated by CYP3A4 and UGT1A9. Three major oxidation products and three major glucuronides have been identified in vivo. Metabolism by rats is mostly by oxidation whereas metabolism by monkeys and humans is mostly by glucuronidation. Metabolism by monkeys closely resembles metabolism by humans and all metabolites found in humans are also found in monkeys. A greater diversity of metabolites has been identified among human in vivo specimens than among in vitro reaction products.Following oral dosing of humans with 14C-bexagliflozin, the 3′-O-glucuronide contributed 32% of the parent AUC and all other metabolites contributed <10%. Of the 91.6% of input radioactivity recovered, 51.1% was in faeces, predominantly as bexagliflozin, and 40.5% was in urine, largely as the 3′-O-glucuronide. Unidentified metabolites contributed 0.27% of the input radiolabel.A quantitative accounting for the metabolism and disposition of bexagliflozin in vivo has been developed.

Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors

The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a–17a) as well as their dehydrate dihydrofuran derivatives (11b–17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 μM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules.

Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations.

Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r2cv) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r2) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors.

Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90% of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Based on their structural features, in this review, these SGLT2 inhibitors are classified as three types: the phenyl/arylmethylphenyl C-glucosides, with an emphasis on the modifications on the proximal and/or the distal phenyl ring, and the spacer; the heteroarylmethylphenyl Cglucosides, with a replacement of the distal phenyl ring by a heterocycle like pyridazine, pyrimidine, thiophene and benzothiophene, thiazole, 1,3,4-thiadiazole, and triazolopyridinone; and the glucose-modified Caryl glucosides, including the glucose C-1 derived O-spiroketals, C-4 gem-difluoro analogues, C-5 and C-6 modified derivatives, dioxa-bicyclo[3.2.1]octane bridged ketals, the thioglucosides, and carbasugars. The structure-activity relationships (SARs) of each type along with their inhibitory potency against human SGLT2 and selectivity over human SGLT1 are discussed.

C-Aryl glucoside SGLT2 inhibitors containing a biphenyl motif as potential anti-diabetic agents.

A series of highly active C-aryl glucoside SGLT2 inhibitors containing a biphenyl motif were designed and synthesized for biological evaluation. Among the compounds tested, compound 16l demonstrated high inhibitory activity against SGLT2 (IC50=1.9 nM) with an excellent pharmacokinetic profile. Further study indicated that the in vivo efficacy of compound 16l was comparable to that of dapagliflozin, suggesting that further development would be worthwhile.

A new and improved process for C-aryl glucoside SGLT2 inhibitors

A practical and scalable synthesis of C-glycosides identified as highly potent sodium-dependent glucose transporter 2 (SGLT2) inhibitors is described. Highlights of the synthetic process are a concise, ten-step synthesis of a structurally complex active pharmaceutical ingredient from a known intermediate via a selective and quantitative addition of an aryl species to the Weinreb amide, and the isomers of undesired ortho-products were avoided during the preparation. The chemistry developed has been applied to prepare SGLT2 inhibitors without recourse to chromatography.

Molecular Modeling Studies of Thiophenyl C-Aryl Glucoside SGLT2 Inhibitors as Potential Antidiabetic Agents.

A QSAR study on thiophenyl derivatives as SGLT2 inhibitors as potential antidiabetic agents was performed with thirty-three compounds. Comparison of the obtained results indicated the superiority of the genetic algorithm over the simulated annealing and stepwise forward-backward variable method for feature selection. The best 2D QSAR model showed satisfactory statistical parameters for the data set (r 2 = 0.8499, q 2 = 0.8267, and pred_r 2 = 0.7729) with four descriptors describing the nature of substituent groups and the environment of the substitution site. Evaluation of the model implied that electron-rich substitution position improves the inhibitory activity. The good predictive 3D-QSAR models by k-nearest neighbor (kNN) method for molecular field analysis (MFA) have cross-validated coefficient q 2 value of 0.7663 and predicted r 2 value of 0.7386. The results have showed that thiophenyl groups are necessary for activity and halogen, bulky, and less bulky groups in thiophenyl nucleus enhanced the biological activity. These studies are promising for the development of novel SGLT2 inhibitor, which may have potent antidiabetic activity.

Optimization of Gaussian Kernel Function in Support Vector Machine aided QSAR studies of C-aryl glucoside SGLT2 inhibitors

The present investigations include utility of latest statistical algorithm Support Vector Machine (SVM) to identify non-linear structure activity relationship between IC50 values and structures of C-aryl glucoside SGLT2 inhibitors. Training dataset consisted of forty molecules and the remaining six molecules were chosen for test set validation. SVM under Gaussian Kernel Function yielded non-linear QSAR models. Forward selection algorithm was applied after pruning and redundancy check on molecular descriptors. Internal validations of QSAR models have been achieved using R CV (2) (LOO), PRESS, SDEP and Y-Scrambling. SVM aided non-linear models are more efficient when optimization of Gaussian Kernel Function was introduced. Non-linear QSAR studies further identified atomic van der Waals volumes, atomic masses, sum of geometrical distances between O..S and degree of unsaturation as molecular descriptors and crucial structural requirements to model IC50 of C-aryl glucoside derivatives.

CoMFA and CoMSIA studies on C-aryl glucoside SGLT2 inhibitors as potential anti-diabetic agents

SGLT2 has become a target of therapeutic interest in diabetes research. CoMFA and CoMSIA studies were performed on C-aryl glucoside SGLT2 inhibitors (180 analogues) as potential anti-diabetic agents. Three different alignment strategies were used for the compounds. The best CoMFA and CoMSIA models were obtained by means of Distill rigid body alignment of training and test sets, and found statistically significant with cross-validated coefficients (q 2) of 0.602 and 0.618, respectively, and conventional coefficients (r 2) of 0.905 and 0.902, respectively. Both models were validated by a test set of 36 compounds giving satisfactory predicted correlation coefficients (r 2 pred) of 0.622 and 0.584 for CoMFA and CoMSIA models, respectively. A comparison was made with earlier 3D QSAR study on SGLT2 inhibitors, which shows that our 3D QSAR models are better than earlier models to predict good inhibitory activity. CoMFA and CoMSIA models generated in this work can provide useful information to design new compounds and helped in prediction of activity prior to synthesis.

Structural Insights into the Active Site of Human Sodium Dependent Glucose Co-Transporter 2: Homology Modelling, Molecular Docking, and 3D - QSAR Studies

Human sodium dependent glucose co-transporter 2 (hSGLT2) is a target for diabetes mellitus type 2 (T2DM). The 3D (three dimensional) homology model of hSGLT2 comprising 14 transmembrane helical domains was constructed and molecular docking of the inhibitors, C-aryl glucoside analogues, into the active site was studied. The 3D-QSAR (quantitative structure activity relationship) analysis was carried out on 43 C-aryl glucoside analogues as a training set. The molecular field analysis (MFA) with G/PLS (genetic partial least-squares) method was used to generate statistically significant 3D-QSAR (r2 = 0.857) based on a molecular field generated using electrostatic and steric probes. The QSAR model was validated using leave-one-out cross-validation, bootstrapping, and randomisation methods, and finally with an external test set comprising 10 inhibitors. The molecular docking studies provide structural insights into the active site and key interactions involved in the binding of inhibitors to hSGLT2 and these results corroborate with the 3D-QSAR analysis that provide the active conformation of inhibitors and the nature of interactive fields important for activity.

Novel thiophenyl C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents

Novel thiophene C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different types of thiophene derivatives were readily prepared. Among the compounds tested, ethylphenyl at the distal ring 71p showed the best in vitro inhibitory activity in this series to date (IC 50 = 4.47 nM) against SGLT2.

1,2,4-Triazinylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors

Novel C-aryl glucoside SGLT2 inhibitors containing triazine motif were designed and synthesized for biological evaluation. Among the compounds assayed, triazine containing methoxy moiety 18 demonstrated the best in vitro inhibitory activity against hSGLT2 in this series to date (<TEX>$IC_{50}$</TEX> = 24.9 nM).

Novel macrocyclic C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents

Novel macrocyclic C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different synthetic routes of macrocyclization were adopted to prepare novel ansa SGLT2 inhibitors. Among the compounds tested, [1,7]dioxacyclopentadecine macrocycles possessing methylthiophenyl at the distal ring 40 or ethoxyphenyl at the distal ring 23 showed the best in vitro inhibitory activity in this series to date (40, IC50=0.778nM and 23, IC50=0.899nM) against hSGLT2.

Glucosides with cyclic diarylpolynoid as novel C-aryl glucoside SGLT2 inhibitors

Novel C-aryl glucoside SGLT2 inhibitors containing cyclic diarylpolynoid motif were designed and synthesized for biological evaluation. Alkylzinc bromides have been efficiently prepared by the direct insertion of zinc metal into alkyl bromides. The organozinc reagents underwent smooth Pd-catalyzed cross-coupling reactions. Subsequent ring closing metathesis using 2nd generation Grubbs catalyst successfully generated novel class of ansa-compounds. These glucosides with cyclic diarylpolynoids demonstrated moderate in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=59.5-103 nM).

Thiazolylmethyl ortho-substituted phenyl glucoside library as novel C-aryl glucoside SGLT2 inhibitors

In order to investigate SAR regarding proximal phenyl ring in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on proximal phenyl ring was conducted. During a series of lead optimization efforts, ortho-allyloxyphenyl 10p or ortho-hydroxyphenyl 11a showed subnanomolar inhibitory activity against hSGLT2.

EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA 1c levels in db/db mice and prolongs the survival of stroke-prone rats

Sodium glucose co-transporter 2 (SGLT2) is a renal type III integral membrane protein that co-transports sodium and glucose from filtrate to epithelium in the proximal tubule. Human subjects with homozygous or compound heterozygous mutations in SLC5A2 exhibit glucosuria without hypoglycemia or other obvious morbidity, suggesting that blockade of SGLT2 has the potential to promote normalization of blood glucose without hypoglycemia in the setting of type 2 diabetes. This report presents the in vitro and in vivo pharmacological activities of EGT1442, a recently discovered SGLT2 inhibitor in the C-aryl glucoside class. The inhibitory effects of EGT1442 for human SGLT1 and SGLT2 were evaluated in an AMG uptake assay and the in vivo efficacy of treatment with EGT1442 was investigated in rats and dogs after a single dose and in db/db mice after chronic administration. The effect of EGT1442 on median survival of SHRSP rats was also evaluated. The IC 50 values for EGT1442 against human SGLT1 and SGLT2 are 5.6 μM and 2 nM, respectively. In normal rats and dogs a saturable urinary glucose excretion was produced with an ED 50 of 0.38 and 0.09 mg/kg, respectively. Following chronic administration to db/db mice, EGT1442 dose-dependently reduced HbA 1c and blood glucose concentration without affecting body mass or insulin level. Additionally, EGT1442 significantly prolonged the median survival of SHRSP rats. EGT1442 showed favorable properties both in vitro and in vivo and could be beneficial to the management of type 2 diabetic patients.

Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors.

Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted.