The aglycones of both phlorizin and dapagliflozin have weak inhibition effects on SGLT-1 and SGLT-2. Two synergistic forces are involved in binding of inhibitors to SGLTs. Different sugars on the aglycone will affect and change the orientation of it in the access vestibule because one of the forces involved in the binding is the binding of sugar to the glucose site. The other force is the binding of the aglycone, which affects the binding affinity of the entire inhibitor.
The discovery of T-1095 led to an investigation of how to enhance potency, selectivity and oral bioavailability by adding various substituents to the glycoside core. As an example we can take the change of o-glycosides to c-glycosides by creating a carbon–carbon bond between the glucose and the aglycone moiety. C-glucosides are more stable than o-glucosides which leads to modified half-life and duration of action. These modifications have also led to more specificity to SGLT-2. C-glucosides that have heterocyclic ring at the distal ring or proximal ring are better when it comes to anti-diabetic effect and physicochemical features all together. C-glucoside bearing thiazole at the distal ring on canagliflozin has shown good physicochemical properties that can lead to a clinical development, but still has the same anti-diabetic activity as dapagliflozin, as shown in tables 1 and 2.
Song and his partners did preparate thiazole compound by starting with carboxyl acid. Working with that, it took them three steps to get a compound like dapagliflozin with a thiazole ring. Inhibitory effects on SGLT-2 of the compounds were tested by Song and his partners. In tables 1, 2, and 3, the IC value changes depending on what compound is in the ring position, in the C-4 region of the proximal phenyl ring, and how the thiazole ring relates.
Many compounds gave different IC value in the ring position in an in vitro activity. For an example there was a big difference if there was an n-pentyl group (IC = 13,3 nM), n-butyl (IC = 119 nM), phenyl with 2-furyl (IC = 0,720) or 3-thiophenyl (IC = 0,772). As seen in table 1, the in vitro activity increases depending on what compound is bonded to the distal ring (given that in the C-4 region of the proximal phenyl ring is a Cl atom).
Table 1: Differences in in vitro activity depending on which compound is bonded to the distal ring.
*comparator to ethyl group (IC = 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). Small methyl groups or other halogen atoms in the C-4 position gave IC ranging from 0.72–36.7 (given that the phenyl with 2-furyl is in the ring position).
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 IC value depending on how the thiazole ring relates (nothing else is changed in the structure (X = Cl, R = phenyl with 2-furyl).