Drugs and glucose handling

❶ Polysaccharides (mostly starch) are ingested

❷ Hydrolysis of polysaccharides by amylases and glucosidases yield monosaccharides

❸ Monosaccharides (e.g. glucose) are absorbed from the small intestine using the SGLT1 transporter. From the gut epithelial cells the glucose enters the blood

❹ Monosaccharides circulate in the blood

❺ When tissues (e.g. muscle, liver, heart…) need glucose they import it from the blood using the GLUT transporters

❻ Glucose remaining in the blood arrives at the kidney and passes into the glomerular filtrate

❼ Rather than be excreted in the urine, glucose in the glomerular filtrate is reabsorbed (ultimately to the blood) using the SGLT2 transporter

What would happen if we inhibited …

… glucosidases?

… SGLT1

… the GLUT transporters?

… SGLT2?

What properties would a glucosidase inhibitor need?

Acarbose

• Isolated from a bacterium

• Ki = 62 μM against MGAM – one of the key gut glucosidases

• This is the bit that binds to the enzyme’s active site

• Almost certainly not selective, but bioavailability is 2%

• Taken with food

• Not recommended by NICE

Acarbose problem

Targeting GLUTs

Inhibiting glucose uptake by tissues

• Targeting the GLUT transporters is a terrible idea because the patient already has an impaired ability to handle glucose blood glucose levels will increase, potentially making the patient’s diabetes worse and you starve some or all tissues of glucose

Targeting SGLT2

Inhibit glucose reuptake in kidney

• Targeting SGLT transporters potentially increases glucose in the urine correspondingly decreases glucose in the blood

• So a drug that inhibits SGLT2 sounds like a good idea. What would we need to make it work?

• We need a drug that

  • Binds SGLT2 more strongly than glucose does

  • Does not inhibit any of the GLUTs (for reasons we’ve already talked about)

  • Does not inhibit SGLT1

• In other words our inhibitor needs to be potent and selective.

Phlorizin and Phloretin

• Phlorizin

  • Derived from apple tree bark

  • Known to produce glycosuria since 1886

  • Identified as SGLT2 inhibitor in 1973

  • Inactive at GLUTs

  • Binds to SGLT2 more potently than glucose does.

  • Explains why the compound gives glycosuria

  • Implies the aglycone contributes to binding.

• Phloretin

  • Inhibits GLUT transporters

Can we improve phlorizin?

But T-1095 never made it to market

• Reasons have never been disclosed, but hydrolysis to glucose and the aglycone is as good a guess as any

• Phlorizin and T-1095 show us that

  • You can gain potency and retain selectivity by changing the aglycone

  • in vitro potency does not always translate to in vivo efficacy

So if the O-glucose bond is the problem

Let’s make some changes

But what about in vivo?

We have been following the discovery of…