Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor

Shimizu, Kazuo; Fujikura, Hideki; Fushimi, Nobuhiko; Nishimura, Toshihiro; Tatani, Kazuya; Katsuno, Kenji; Fujimori, Yoshikazu; Watanabe, Shinjiro; Hiratochi, Masahiro; Nakabayashi, Takeshi; Kamada, Noboru; Arakawa, Koichi; Hikawa, Hidemasa; Azumaya, Isao; Isaji, Masayuki

doi:10.1016/j.bmc.2021.116033

Cited by 8 publications

(9 citation statements)

References 33 publications

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“…After T-1095, other O -glucosides were synthesized as pro-drugs, such as sergliflozin [ 69 ] or remogliflozin [ 70 ]. However, O-glucosides-SGLT2i were still metabolically unstable due to their recognition and cleavage by the β-glucosidases in circulation [ 9 ].…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Feijóo‐Bandín

Aragón-Herrera

Otero-Santiago

et al. 2022

IJMS

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Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

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Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Feijóo‐Bandín

Aragón-Herrera

Otero-Santiago

et al. 2022

IJMS

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“…Finally, the introduction of the isopropyl group on N-1 furnished remogliflozin, which showed activity similar to compound 5c and better selectivity for SGLT-2. 60 Interestingly, the introduction of a methyl group on N-2 reduced significantly the effectiveness, probably because its presence induces a conformation of the glucoside group inappropriate for the interaction with the target. 60 Remogliflozin is a selective SGLT-2 inhibitor (K i hSGLT-1/ K i hSGLT-2 = 365; IC 50 hSGLT-1/IC 50 hSGLT-2 = 902).…”

Section: Sglt-1 and Sglt-2 Inhibitors: From Discovery To Development ...mentioning

confidence: 99%

“…60 Interestingly, the introduction of a methyl group on N-2 reduced significantly the effectiveness, probably because its presence induces a conformation of the glucoside group inappropriate for the interaction with the target. 60 Remogliflozin is a selective SGLT-2 inhibitor (K i hSGLT-1/ K i hSGLT-2 = 365; IC 50 hSGLT-1/IC 50 hSGLT-2 = 902). Following oral administration in animal models, it showed a glucose-lowering effect by increasing UGE in a dose-dependent manner, independently of insulin levels, without increasing the risk of hypoglycemia.…”

Section: Sglt-1 and Sglt-2 Inhibitors: From Discovery To Development ...mentioning

confidence: 99%

“…However, compound 5a was found inactive on hSGLT-2 expressed by COS-7 cells transiently transfected with hSGLT expression plasmids . Therefore, supposing that the active drug was the corresponding glucoside metabolite, O -glucoside 5b was synthesized and proved to be an excellent inhibitor of SGLT-2 transporter. , …”

Section: Sglt-1 and Sglt-2 Inhibitors: From Discovery To Development ...mentioning

confidence: 99%

“… Regarding the pattern of substitution of the distal aromatic ring, an isopropyloxy group in the para position provided compound 5c endowed with good activity and selectivity (IC 50 hSGLT-1/IC 50 hSGLT-2 = 278) but unfortunately lacking the appropriate oral bioavailability. Finally, the introduction of the isopropyl group on N-1 furnished remogliflozin, which showed activity similar to compound 5c and better selectivity for SGLT-2 . Interestingly, the introduction of a methyl group on N-2 reduced significantly the effectiveness, probably because its presence induces a conformation of the glucoside group inappropriate for the interaction with the target …”

Section: Sglt-1 and Sglt-2 Inhibitors: From Discovery To Development ...mentioning

confidence: 99%

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Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives

Maccari

Ottanà

2022

J. Med. Chem.

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Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure− activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.

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Overview of the current procedures in synthesis of heparin saccharides

Zhao,

Zhang,

Kan

et al. 2024

Carbohydrate Polymers

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Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor

Cited by 8 publications

References 33 publications

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives

Overview of the current procedures in synthesis of heparin saccharides

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