Diabetes Medicinal Chemistry

What are key historical milestones in diabetes?

• 1500 BC: First description (Ebers Papyrus)

• 1815: Glucose identified in urine

• 1869: Islets of Langerhans discovered

• 1889: Pancreas linked to diabetes

• 1922: First successful insulin treatment

What are the main drug classes for type 2 diabetes?

Oral:

• Metformin

• Sulfonylureas

• DPP-4 inhibitors

• TZDs

• SGLT2 inhibitors

Injectable:

• GLP-1 analogues

• Insulin

What is metformin and why is it first-line for type 2 diabetes?

• Biguanide antihyperglycaemic

• First-line for type 2 diabetes » due to low risk of hypoglycaemia

How does metformin work?

• Inhibits mitochondrial energy production → so ↓ ATP

• Activates AMP-activated protein kinase (AMPK)

• AMPK effects:

  • ↓ gluconeogenesis in the liver (glucose production)

  • ↑ insulin sensitivity = so increases glucose uptake in muscle

What is the origin of metformin?

• Derived from galegine (plant compound)

• Used since 1950s

• Related drug phenformin withdrawn (lactic acidosis)

How do sulfonylureas work?

• Stimulate pancreatic beta cells

• Close K⁺ channels → depolarisation

• ↑ Ca²⁺ influx → insulin release

= ↑ insulin production

What is a key risk of sulfonylureas?

• Hypoglycaemia

• Weight gain

What structural features affect sulfonylurea activity?

• Para-substituted benzene ring = ↑ activity

• Larger N-substituents = ↑ lipophilicity & activity

• Too large (>12 carbons) = ↓ activity

Example of a sulfonyl urea

Chlorpropamide

• Developed by Pfizer

• Approved by the FDA to treat T2DM in 1958

• Brand name is Diabinese.

• Taken by mouth to control high blood sugar levels in individuals with non-insulin-dependent diabetes mellitus (NIDDM)

• Chlorpropamide belongs to the class of sulfonylurea drugs that act as insulin secretagogues.

• Its primary mechanism of action involves stimulating the release of insulin from the β cells located in the pancreas.

How do thiazolidinediones (TZDs) work?

• Activate PPAR-γ receptor

• ↑ insulin-responsive gene expression

• ↓ insulin resistance

What is the history of TZDs?

• Ciglitazone → first antihyperglycaemic TZD, toxic

• Troglitazone → liver toxicity

• Rosiglitazone → withdrawn (heart risk)

• Pioglitazone → currently used

What is the structure of TZDs

• TZD acidic head

• Lipophilic tail

• Central phenyl ring

• Two linker chains

How do TZDs bind to the PPARy receptors?

• Hydrogen bonds with the P₁ hydrophilic binding pocket present in arm I of the active site

• Lipophilic tail binds to binding sites in arm II and arm III via:

  • Hydrophobic interactions

  • π–π stacking

• The aliphatic linking chains act as spacers in order to orientate the acidic TZD head and lipophilic tail into their binding pockets.

How do SGLT2 inhibitors work?

• Inhibits sodium-glucose transport proteins in the nephrons

• So blocks glucose reabsorption in kidneys

• ↑ glucose excretion in urine

= decrease blood glucose levels

Give examples of SGLT2 inhibitors

• Canagliflozin

• Dapagliflozin

• Empagliflozin

What are incretin hormones?

• Hormones that are released after eating to help lower blood sugar levels.

• They are released by the gut and stimulate the pancreas to release insulin

Purpose of incretin secretion?

• ↑ insulin secretion

• ↓ glucose production

• Slow gastric emptying

• ↓ appetite

What is exenatide?

• Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1)

• Longer half-life in vivo than GLP-1

How is exantide used to treat type 2 diabetes?

• As an add-on to metformin

• or a combination of metformin + sulfonylurea or thiazolidinediones

Exenatide is a synthetic version of…

• Exendin-4

• A peptide found in the venom of the Gila monster

Why can incretins not be used therapeutically?

• The half life of a functional GLP-1 molecule is less than 2 minutes

• So it will be rapidly cleared from body systems

What is responsible for the clearance of incretin hormones?

• DPP-4

• So inhibition of DPP-4 to prevent the fast decay of incretins appears to be a promising therapeutic goal in the treatment of diabetes

DPP-4 Inhibitors

• Prolong the activity of incretin hormones

• Enhancing their insulin secretion

Example of a DPP-4 Inhibitor

sitagliptin

Mechanism of action of sitagliptin?

• Bind to DPP-4 enzyme active site

• Inhibit enzyme activity

• Prolong incretin action

Structure of DPP-4 Inhibitors

• Heterocyclic ring

• Linker / spacer

• Aryl group