Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry

Abstract

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

SGLT2 Inhibitors and nephroprotection in diabetic kidney disease: From mechanisms of action to the latest evidence in the literature

“…Between the years 1980 and 1990, sodiumglucose cotransporters-1 (SGLT1) and sodium-glucose cotransporters-2 (SGLT2) inhibitors were identi ied, as well as the bene its of phlorizine in the diabetic population primarily in animal models. In diabetic rats with to 90% pancreatectomy, it was discovered that phlorizine normalized fasting and postprandial glucose levels, with additional bene its in insulin resistance [14,15]. In contrast to the previously mentioned, phlorizine was not thought of a candidate for glucose lowering therapy, given a great number of limitations.…”

“…Given its similar properties to Cinchona extracts and weeping willow, it was proposed as a reasonable candidate to treat fever, some infectious diseases and even malaria. Approximately 50 years later, its glucosuric capacity at high doses was discovered [11,14,15]. It was also suggested that phlorizine induced diabetes in canine models, given that it caused similar symptoms with its chronic administration (glucosuria, polyuria and weight loss) [15].…”

“…Studies regarding phlorizine continued in the next few decades focusing on renal physiology, and 40 years later it was discovered that active glucose transport responsible for the reabsorption of glucose was located in the brush border membrane of the proximal tubule, site where phlorizine had its action. It was then when the kidney started to be conceptualized as an important organ in the metabolism of glucose, contemplating it as a possible target in glucose lowering therapy [13][14][15].…”

“…SGLT2 inhibitors also pose an antihypertensive effect, which is very relevant in the context of diabetic kidney disease, given the control of blood pressure is a challenge in patients with chronic kidney disease and hypertension plays a key role in albuminuria and in the progression of chronic kidney disease. With the use of SGLT2 inhibitors the blood pressure lowering activity is reached without compensatory increase in the heart rate [14]. SGLT2 inhibitors are capable of decreasing systolic and diastolic blood pressure approximately 4 to 5 mmHg and 2 mmHg, respectively [8,14].…”

Discovery of Novel N-Glycoside and Non-Glycoside hSGLT2 Inhibitors for the Treatment of Type 2 Diabetes Mellitus

“…Over the past few years, since the crystal structure of hSGLT2 is not yet available, the strategies for developing new hSGLT2 inhibitors are limited to chemical synthesis, structure-activity relationships (SAR) analysis, and lead modification [26] [27] [28]. These strategies would be high cost and time-consuming in the process of new drug development and the results are also limited to the highly structural similarity.…”