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

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.

C‐Aryl Glycosylation via Interrupted Pummerer Rearrangement†

“…[ 27 ] Sotagliflozin is an inhibitor of both SGLT1 and SGLT2, and its oxygen at position one can be substituted with sulfur. [ 28 ] Under our reaction conditions, we achieved 11a (68%), 11b (72%), and 11c (69%), demonstrating the feasibility of the protocol in Scheme 2. Scale‐up preparation of 11c further showed the practicability.…”

C-Aryl Glycosylation via Interrupted Pummerer Rearrangement

“…24 Sotagliflozin is an inhibitor of both SGLT1 and SGLT2, and its oxygen at position one can be substituted with sulfur. 25 Under our reaction conditions, we achieved11a (68%), 11b (72%), and 11c (69%), demonstrating the feasibility of the protocol. Scale-up preparation of11c further shown the practicability.…”

Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections

“…We also obtained a cocrystal structure of 69 bound to FmlH, which explains how we were able to use fluorine substituents in place of sulfonamides without sacrificing a significant amount of binding affinity to FmlH. Using tPSA to predict both CNS and intestinal oral permeability has been applied successfully to many other small-molecule drugs , including the glycomimetic drugs including the P2Y12 antagonist Ticagrelor, the Galectin-3 inhibitor Selvigaltin, and most recently SGLT-2 inhibitors. − This learned strategy, to increase log D and decrease tPSA and/or CMR of the aglycone, in this case by adding aryl fluorine or fluorinated alkyl groups for increasing cellular permeability and oral bioavailability, can be applied to other glycoside-based drugs . In summary, we have developed ortho -biphenyl galactoside 69 (AM4085) as a promising lead candidate worthy of further potency optimization and biological evaluation in advanced preclinical studies in the treatment of chronic UTIs of the bladder and kidney.…”