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Allopathic Medicines
Published in Varma H. Rambaran, Nalini K. Singh, Alternative Medicines for Diabetes Management, 2023
Varma H. Rambaran, Nalini K. Singh
Several specific and potent SGLTi drugs have undergone preclinical testing, most of which are glucosides that are structurally related to the lead drug: phlorizin. O-glucosides, such as sergliflozin etabonate (Figure 2.17a) and remogliflozin etabonate (Figure 2.17b), are strategically administered in the prodrug form of the biologically active sergliflozin A and remogliflozin to avoid degradation by β-glucosidase in the small intestine (Nair and Wilding 2010).Structural formulae of O-glucosides: (a) sergliflozin etabonate and (b) remogliflozin etabonate.
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The chemical structures of dapagliflozin 230, canagliflozin 231, empagliflozin 232 and ipragliflozin 233 present a C-glycosidic linkage between the glucose moiety and the aglycon; luseogliflozin 235 also possess the C-glycosidic bond, but now between the aglycon and the corresponding 5-thio-D-glucopiranose. Remogliflozin etabonate 236 is the only member of the family possessing the classical O-linkage, while tofogliflozin 234 is a spiranic compound, so that C- and O-linkages are simultaneously present.
An update of SGLT1 and SGLT2 inhibitors in early phase diabetes-type 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2019
Ernest Adeghate, Sahar Mohsin, Faisal Adi, Fares Ahmed, Ali Yahya, Huba Kalász, Kornelia Tekes, Ernest A. Adeghate
Remogliflozin etabonate is a pro-drug of remogliflozin, a selective inhibitor of SGLT2 protein. It prevents the reabsorption of glucose from the epithelium of the PCT. It is a drug developed by Avolynt Inc (Research Triangle Park, North Carolina, USA). Remogliflozin is currently undergoing clinical trials for the treatment of T2DM and non-alcoholic steatohepatitis. Remogliflozin has been reported to reduce blood glucose and HbA1c levels [60]. The phase 2b trial was completed in 2018 [61]. It is well tolerated but with a relatively short half-life of just 2–4 h [62,63]. In contrast to the advantages of remogliflozin, it also causes side effects (e.g. urinary and genital tract fungal infections, syncope) [64] that are similar to those seen with other SGLT2 inhibitors. Although remogliflozin was approved for the treatment of T2DM in India on July 2019, it is not yet licensed for use in the USA. The daily dosage of remogliflozin 200 mg is two doses [63]. Figure 2, Table 2
Ipragliflozin and sodium glucose transporter 2 inhibitors to reduce liver fat: will the prize we sought be won?
Published in Expert Opinion on Pharmacotherapy, 2018
Kalliopi Pafili, Efstratios Maltezos, Nikolaos Papanas
Sodium glucose co-transporter 2 inhibitors (SGLT2is) are modern antidiabetic agents which induce glycosuria by blockade of proximal renal tubule glucose reabsorption [10,11]. These agents manifest pleiotropic beneficial actions: attenuation of hyperglycemia, hypertension, and albuminuria and reduction of body weight and serum uric acid along with nephroprotection attributed among others to reduction of hyperfiltration and intraglomerular pressure [19,20]. With respect to NAFLD, tofogliflozin administered (for 3–5 weeks) to obese diabetic mice was associated with decrease of liver weight and IHLC and with improvement of hepatic steatosis along with attenuation of body weight gain (body weight of control group increased by 8.6 ± 0.5 g over 5 weeks) [12]. Four-week treatment with remogliflozin etabonate in a mouse NAFLD model was also reported to reduce plasma aminotransferases, liver weight, and IHLC, but without change in body weight gain [13]. Similarly, in another study, luseogliflozin decreased liver weight and serum alanine aminotransferase levels in NASH mice, but again body weight was not affected [13]. Unfortunately, this reduction in alanine aminotransferase can only be considered as a surrogate marker of NASH and, hence, far too indirect to state that this is an effective therapy.
Sodium–glucose cotransporter 2 inhibitors for the management of type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2021
Maka Siamashvili, Stephen N. Davis
The vast majority of glucose reabsorption from the kidneys’ glomerular filtrate is carried out by membrane proteins (transporters) collectively called: sodium−glucose cotransporter (SGLT) 2. These proteins are the newest therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Inhibiting SGLT2 results in reduced glucose reabsorption in the kidney’s proximal tubule, increased glucosuria (a pharmacodynamic effect), and thus improved glycemia, which is independent from changes in insulin resistance or beta cell function [1,2]. SGLT2 is only present in the kidney, which makes SGLT2 inhibitors highly selective for this organ. The four members of the class: empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin are currently approved in the USA, Europe, Japan, and many other parts of the world. Ipragliflozin is approved in Japan and Russia, luseogliflozin and tofogliflozin in Japan, remogliflozin etabonate in India, and sotagliflozin in the European Union for type 1 diabetes. These oral agents all have significant effects to inhibit SGLT2 (empagliflozin and ertugliflozin being the most selective for SGLT2 versus SGLT1 and canagliflozin – least selective while sotagliflozin being a dual SGLT1 and SGLT2 inhibitor) [3]. Besides glycemic efficacy (glycated hemoglobin (HbA1c) reduction: ≈ 1%) and a favorable safety profile with low risk of hypoglycemia, these drugs have also demonstrated cardiovascular (CV) and renal benefits by improving blood pressure, body weight, endothelial function, and potentially lipid parameters. Inhibition of SGLT2 appears to stimulate efferent renal nerves that trigger increase in hepatic glucose production, which protects against hypoglycemia [4].