Discovery and development of gliflozins: Difference between revisions

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== Drug development ==

Phlorizin consists of glucose [[Moiety (chemistry)|moiety]] and two [[aromatic rings]] ([[aglycone]] moiety) joined by an [[alkyl]] spacer. Initially, phlorizin was isolated for treatment of fever and infectious diseases, particularly [[malaria]]. 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. In the early 1990s, sodium/glucose cotransporter 2 was fully characterized, so the mechanism of phlorizin became of real interest. In later studies it was said~~{{By whom|date=January 2018}}~~ that sugar-blocking effects of phlorizin was due to inhibition of the sodium/glucose cotransporter proteins.

Phlorizin consists of glucose [[Moiety (chemistry)|moiety]] and two [[aromatic rings]] ([[aglycone]] moiety) joined by an [[alkyl]] spacer. Initially, phlorizin was isolated for treatment of fever and infectious diseases, particularly [[malaria]]. 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. In the early 1990s, sodium/glucose cotransporter 2 was fully characterized, so the mechanism of phlorizin became of real interest. In later studies it was said that sugar-blocking effects of phlorizin was due to inhibition of the sodium/glucose cotransporter proteins.

Most of the reported SGLT-2 inhibitors are [[glucosides|glucoside]] analogs that can be tracked to the o-aryl glucoside found in the nature. The problem with using [[o-glucosides]] as SGLT-2 inhibitors is instability that can be tracked to degradation by [[Beta-glucosidase|β-glucosidase]] in the small intestine. Because of that, o-glucosides given orally have to be [[prodrug]] esters. 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. The first discovered c-glucoside was the drug [[dapagliflozin]]. Dapagliflozin was the first highly selective SGLT-2-inhibitor approved by the [[European Medicines Agency]]. All SGLT-2 inhibitors in clinical development are [[prodrugs]] that have to be converted to its active ‘A’ form for activity.

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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. 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 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.

@@ Line 36: / Line 36: @@
 == Drug development ==
-Phlorizin consists of glucose [[Moiety (chemistry)|moiety]] and two [[aromatic rings]] ([[aglycone]] moiety) joined by an [[alkyl]] spacer. Initially, phlorizin was isolated for treatment of fever and infectious diseases, particularly [[malaria]]. 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. In the early 1990s, sodium/glucose cotransporter 2 was fully characterized, so the mechanism of phlorizin became of real interest. In later studies it was said{{By whom|date=January 2018}} that sugar-blocking effects of phlorizin was due to inhibition of the sodium/glucose cotransporter proteins.
+Phlorizin consists of glucose [[Moiety (chemistry)|moiety]] and two [[aromatic rings]] ([[aglycone]] moiety) joined by an [[alkyl]] spacer. Initially, phlorizin was isolated for treatment of fever and infectious diseases, particularly [[malaria]]. 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. In the early 1990s, sodium/glucose cotransporter 2 was fully characterized, so the mechanism of phlorizin became of real interest. In later studies it was said that sugar-blocking effects of phlorizin was due to inhibition of the sodium/glucose cotransporter proteins.
 Most of the reported SGLT-2 inhibitors are [[glucosides|glucoside]] analogs that can be tracked to the o-aryl glucoside found in the nature. The problem with using [[o-glucosides]] as SGLT-2 inhibitors is instability that can be tracked to degradation by [[Beta-glucosidase|β-glucosidase]] in the small intestine. Because of that, o-glucosides given orally have to be [[prodrug]] esters. 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. The first discovered c-glucoside was the drug [[dapagliflozin]]. Dapagliflozin was the first highly selective SGLT-2-inhibitor approved by the [[European Medicines Agency]]. All SGLT-2 inhibitors in clinical development are [[prodrugs]] that have to be converted to its active ‘A’ form for activity.
@@ Line 57: / Line 57: @@
 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. 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 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.