Lecture 21 - Chemistry of Oral Antidiabetics Flashcards
What are the classes of oral antidiabetics?
biguanides sulfonylureas glitazone gliptins GLP-1 agonists (not oral)
What are the biguanides?
metformin
buformin
phenformin
Structure of biguanides?
highly charged, highly hydrophilic and very basic
Effect of metformin?
mainly due to the inhibition of hepatic glucose output
What is the presumed site of metformin function?
the liver
Metabolism of metformin?
not metabolised and is unchanged throughout the journey in the body
What is most used to treat T2D?
Metformin
Why were buformin and phenformin withdrawn?
they had toxicity associated and caused acidosis
What is the high basic pKa of biguanides due to?
resonance forms of biguanide stabilising the conjugate acid positive charge so the equilibrium lies to the left
Route of metformin?
orally active so must be active uptake mechanism
1st generation sulfonylureas?
chlopromide
tolbutamide
2nd generation sulfonylureas?
gliquidone
What is the NH attached to sulphur and carbonyl in sulfornylureas?
weakly acidic
Other sulfonylureas?
glibenclamide and glimepiride
gliclazide and glipizide
What are the oldest hypoglycaemia agents?
sulfonylureas
How do sulfonylureas work?
stimulate insulin secretion by binding to sulfonylurea receptor 1 (SUR-1) sub unit of the ATP sensitive K channels in the beta cell plasma membrane
How are sulfonylureas classes?
first and second generation
What are sulfonylureas associated with?
weight gain and hypoglycaemia
Can sulfonylureas be used with metformin?
yes
Meglitinides?
nateglinide
repaglinide
How do meglitinides work?
in a similar manner to sulfonylureas
stimulate insulin secretion by binding to sulfonylurea receptor 1 (SUR-1) sub unit of the ATP sensitive K channels in the beta cell plasma membrane
What do meglitinides have?
weaker binding and dissociation from the SUR-1 binding site of the ATP sensitive K channel
Glitazones?
rosiglitazone
pioglitazone
What do glitazones posses?
the thiazolidinedione moiety
How to glitazones work?
activate the gamma isoform of the peroxisome proliferator-activated receptor PPAR gamma
What does activation of PPAR gamma do?
improve insulin sensitivity
GLP-1 agonists?
exenatide
not oral
Why are GLP-1 agonists not oral?
huge molecular weight, pKa etc
it is a large polypeptide
do not satisfy Lipinski’s rule of 5
What is exenatide?
a synthetic mimic for GLP-1
What is exenatide classed as?
an incretin mimic
What breaks down GLP-1?
DPP4
Why does DPP4 not break down exenatide?
it is slightly different so is not broken down as fast but stimulates insulin release
How is exenatide given?
as a subcutaneous injection
Gliptins?
DPP4 inhibitors
sitagliptin
vildagliptin
What are gliptins?
DPP4 inhibitors
What does DPP4 do?
acts on GLP-1 and GIP to inactivate the
When are GLP-1 and GIP released?
after food intake in the intestine and stimulate insulin production
What does inhibition of DPP4 do?
stimulates insulin secretion
What did the SIPBS drug cause?
weight loss and uptake of glucose in mice
possible interaction with phosphatases in beta cells
some toxicity in mice
