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Review
. 2022 Aug 25;65(16):10848-10881.
doi: 10.1021/acs.jmedchem.2c00867. Epub 2022 Aug 4.

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

Rosanna Maccari  1 , Rosaria Ottanà  1
Affiliations
Review

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

Rosanna Maccari et al. J Med Chem. .

Abstract

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of phlorizin and selected 4-dehydroxyphlorizin derivatives.
Figure 2
Figure 2
Structures and development of sergliflozin and remogliflozin.
Figure 3
Figure 3
Development of meta-diarylmethane C-glucoside hSGLT-2 inhibitors.
Figure 4
Figure 4
- Dapagliflozin analogues obtained by modifying the distal aryl moiety.
Figure 5
Figure 5
Dapagliflozin- and canagliflozin-derived aryl/heteroaryl C-glucosides.
Figure 6
Figure 6
Development of ipragliflozin.
Figure 7
Figure 7
Structures of selected 3-[(azulen-2-yl)methyl]phenyl C-glucosides.
Figure 8
Figure 8
General structures of macrocyclic C-glycoside derivatives.
Figure 9
Figure 9
Design and SARs of tofogliflozin and derivatives.
Figure 10
Figure 10
Design of luseogliflozin.
Figure 11
Figure 11
SARs of ertugliflozin-derived SGLT-2 inhibitors.
Figure 12
Figure 12
Examples of sugar-modified dapagliflozin derivatives.
Figure 13
Figure 13
Structures of representative xylose-derived SGLT inhibitors.
Figure 14
Figure 14
Development of dual SGLT-1/SGLT-2 inhibitors.
Figure 15
Figure 15
4-Benzyl-1H-pyrazol-3-yl β-d-glycopyranosides endowed with selective hSGLT-1 inhibitory activity.
Figure 16
Figure 16
Sotagliflozin-derived low adsorbable dual SGLT-1/SGLT-2 inhibitors.
Figure 17
Figure 17
Design of new low adsorbable dual SGLT-1/SGLT-2 inhibitors.
Figure 18
Figure 18
Structures of selected aniline-N-glucosides and heteroaromatic-N-glucosides.
Figure 19
Figure 19
Structures of selected 3-benzylindolyl-N-glucosides.
Figure 20
Figure 20
Structures of selected N-linked β-d-xylosides.
Figure 21
Figure 21
Structures of selected C-indolylxylosides.
Figure 22
Figure 22
Selected 3-(4-cyclopropylbenzyl)-1H-indole N-glucosides.
Figure 23
Figure 23
Selected 4-chloro-3-(4-cyclopropylbenzyl)-1H-indole N-glycosides modified at the C-6 position of the sugar moiety.
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