Discovery and development of gliflozins: Difference between revisions

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The [[aglycones]] of both phlorizin and dapagliflozin have weak inhibition effects on SGLT-1 and SGLT-2. Two [[Synergy#Drug synergy|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{{When|date=January 2018}} 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.~~<ref name="Idris og Donnelly, 2009" />~~ C-glucosides that have [[heterocyclic]] ring at the distal ring or proximal ring are better when it comes to anti-diabetic effect and [[Physical chemistry|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.

The discovery of T-1095 led to an investigation{{When|date=January 2018}} 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 [[Physical chemistry|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<sub>50</sub> 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.

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 The [[aglycones]] of both phlorizin and dapagliflozin have weak inhibition effects on SGLT-1 and SGLT-2. Two [[Synergy#Drug synergy|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{{When|date=January 2018}} 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.<ref name="Idris og Donnelly, 2009" /> C-glucosides that have [[heterocyclic]] ring at the distal ring or proximal ring are better when it comes to anti-diabetic effect and [[Physical chemistry|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.
+The discovery of T-1095 led to an investigation{{When|date=January 2018}} 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 [[Physical chemistry|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<sub>50</sub> 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.