Discovery and development of gliflozins: Difference between revisions

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=== T-1095 ===

[[File:T-1095.svg|thumb|The structure of T-1095]]

Because Phlorizin is a nonselective inhibitor with poor oral bioavailability, a phlorizin derivative was synthesised and called T-1095. 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.~~<ref name="Nair og Wilding, 2010" /><ref name="Idris og Donnelly, 2009" />~~ By inhibiting [[SGLT-1]] and [[SGLT-2]], urinary glucose excretion increased in diabetic animals. T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1~~<ref name="Nair og Wilding, 2010" />~~ but non-selective SGLT inhibitors may also block [[Glucose transporter|glucose transporter 1]] (GLUT-1). Because 90% of filtered glucose is reabsorbed through SGLT-2, research has focused specifically on SGLT-2. Inhibition of SGLT-1 may also lead to the genetic disease [[glucose-galactose malabsorption]], which is characterized by severe diarrhea.

Because Phlorizin is a nonselective inhibitor with poor oral bioavailability, a phlorizin derivative was synthesised and called T-1095. 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. By inhibiting [[SGLT-1]] and [[SGLT-2]], urinary glucose excretion increased in diabetic animals. T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1 but non-selective SGLT inhibitors may also block [[Glucose transporter|glucose transporter 1]] (GLUT-1). Because 90% of filtered glucose is reabsorbed through SGLT-2, research has focused specifically on SGLT-2. Inhibition of SGLT-1 may also lead to the genetic disease [[glucose-galactose malabsorption]], which is characterized by severe diarrhea.

=== ISIS 388626 ===

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 === T-1095 ===
 [[File:T-1095.svg|thumb|The structure of T-1095]]
-Because Phlorizin is a nonselective inhibitor with poor oral bioavailability, a phlorizin derivative was synthesised and called T-1095. 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.<ref name="Nair og Wilding, 2010" /><ref name="Idris og Donnelly, 2009" /> By inhibiting [[SGLT-1]] and [[SGLT-2]], urinary glucose excretion increased in diabetic animals. T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1<ref name="Nair og Wilding, 2010" /> but non-selective SGLT inhibitors may also block [[Glucose transporter|glucose transporter 1]] (GLUT-1). Because 90% of filtered glucose is reabsorbed through SGLT-2, research has focused specifically on SGLT-2. Inhibition of SGLT-1 may also lead to the genetic disease [[glucose-galactose malabsorption]], which is characterized by severe diarrhea.
+Because Phlorizin is a nonselective inhibitor with poor oral bioavailability, a phlorizin derivative was synthesised and called T-1095. 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. By inhibiting [[SGLT-1]] and [[SGLT-2]], urinary glucose excretion increased in diabetic animals. T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1 but non-selective SGLT inhibitors may also block [[Glucose transporter|glucose transporter 1]] (GLUT-1). Because 90% of filtered glucose is reabsorbed through SGLT-2, research has focused specifically on SGLT-2. Inhibition of SGLT-1 may also lead to the genetic disease [[glucose-galactose malabsorption]], which is characterized by severe diarrhea.
 === ISIS 388626 ===