Discovery and development of gliflozins
The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria.
SGLT-2 is mainly expressed in the S-1 and S-2 segments of the proximal renal tubules where the majority of filtered glucose is absorbed.
They work independently of insulin and can reduce glucose levels without causing hypoglycemia or weight gain.
Which physician originally thought that diabetes mellitus was a renal disorder because of glucose discharged in urine is apparently now lost to history.
Every day approximately 180 grams of glucose are filtered through the glomeruli and lost into the primary urine in healthy adults, but more than 90% of the glucose that is initially filtered is reabsorbed by a high capacity system controlled by SGLT-2 in the early convoluted segment of the proximal tubules.
[10][11][12] Phlorizin seemed to have very interesting properties and the results in animal studies were encouraging, it improved insulin sensitivity and in diabetic rat models it seemed to increase glucose levels in urine and also normal glucose concentration in plasma occurred without hypoglycemia.
According to Michael Nauck and his partners, studies were made in the 1950s on phlorizin that showed that it could block sugar transport in the kidney, small intestine, and a few other tissues.
These prodrugs go through changes in the body leading to carbon–carbon bond between the glucose and the aglycone moiety so c-glucoside are formed from the o-glucosides.
C-glucosides have a different pharmacokinetic profile than o-glucosides (e.g. half-life and duration of action) and are not degraded by the β-glucosidase.
T-1095 is a methyl carbonate prodrug that is absorbed into the circulation when given orally, and is rapidly converted in the liver to the active metabolite T-1095A.
T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1[1] but non-selective SGLT inhibitors may also block glucose transporter 1 (GLUT-1).
[9][17] According to preliminary findings of a novel method of SGLT-2 inhibition, the antisense oligonucleotide ISIS 388626 improved plasma glucose in rodents and dogs by reducing mRNA expression in the proximal renal tubules by up to 80% when given once a week.
A study results on long-term use of ISIS 388626 in non-human primates observed more than 1000 fold increase in glucosuria without any associated hypoglycemia.
The authors concluded that "Before the concept of antisense-mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations.
"[19] Michael Nauck recounts that meta-analyses of studies about the activity of SGLT-2 inhibitors in glycemic control in type 2 diabetes mellitus patients shows improvement in the control of glucose, when compared with placebos, metformin, sulfonylurea, thiazolidinediones, insulin and more.
[4] The results, summed up, were that 10 mg of dapagliflozin showed more effect than placebo in the control of glucose, when given for 24 weeks.
However, no inferior efficacy of 10 mg dapagliflozin was shown when used as an add-on therapy to metformin, compared with glipizide after use for 52 weeks.
10 mg of dapagliflozin showed neither inferior efficacy compared with metformin when both of the medicines were given as monotherapy for 24 weeks.
[citation needed] Song and his partners did preparate thiazole compound by starting with carboxyl acid.
*comparator to ethyl group (IC50 = 16,7) In table 2, the in vitro activity changes depending on the compound in the C-4 region of the proximal phenyl ring (X).
[3] Table 2: Differences in in vitro activity depending on what compound is in the C-4 region of the proximal phenyl ring.
Table 3: Difference in the IC50 value depending on how the thiazole ring relates (nothing else is changed in the structure (X = Cl, R = phenyl with 2-furyl).
