SL22106-Lec Natural Products: (aspirin, digoxin, exenatide)

Sources of medicines

Exenatide- lizards

Aspirin- trees

Digoxin- plants

Exenatide

Gila monster

Non fatal

Toxic venom contain bioactive peptides which lower blood sugar

Bioactive peptides

Exendin-4

Good drug target for anti diabetic drugs

Extracted from glands (exocrine) and lowers blood sugar (endocrine)

Exendin-4 and GLP-1

exendin-4 is similar to GLP-1

due to similar active site

therefore similar biological activity

SAR- structural activity relationships

GLP-1

Peptide hormone

Primarily produced in the intestine (ileum and colon)

GLP-1 cleaving

Two active peptides

GLP-1 7-36 amide and minor GLP-1 7-37

What cleaves active GLP peptides

DPP-4

potentiates GLP-1l

What other sites does GLP-1 have an effect on

Great density of GLP-1 receptors in the pancreas but also found in CNS and stomach

GLP-1 agonists and DPP inhibitors

• GLP-1 receptor agonists

  These injectable drugs stimulate GLP-1 receptor activity. They can improve blood pressure and lipids, and may lead to weight loss. Common side effects include nausea, upper respiratory tract infections, and headaches.

• DPP-4 inhibitors

  These orally administered drugs increase GLP-1 levels. They can reduce HbA1c by 0.5–0.8%. Common side effects include upper respiratory tract infections, nasopharyngitis, and headaches. 

GLP-1 and food effects

Eat food

GI tract

Intestinal secretion of GLP-1

Incretin action

Stimulate insulin release

inhibit glucagon release

slow gastric emptying- causes nausea

also CNS activity

Why does GLP-1 have to be injected

Can’t be taken orally

has to be injected

How is incretin mimicked by GLP1 agonists as treatment for T2DM

Exenatide SC BD

alanine and lysine resides of GLP were replaced to 2 aminobutyric acid and arginine in semaglutide which prevents breakdown by DPP-4 and increases biological half-life to a useful level

Lysine

Acylated with steric acid

promoted binding to plasma albumin

extends half life to 7 days

Liraglutadide

Lys to Arg

Add Hexadecanoyl group

binds to plasma protein

extends the half life

Semaglutide lipinski

Peptide- can’t be delivered orally due to lipinski

< 5H bond donors

<10 H-bond acceptors

MW< 500

Log P <5

semglutide structure

4000 Da MW

Long half life

very potent

SNAC

Added to semaglutide

Increases pH and increases membrane permeability to aid absorption

allows for oral delivery

GLP-1 agonist issues

Stock shortages due to alternative purposes of the drug

How does GLP-1 reduce blood sugar

Mimics action of GLP-1 hormone

GLP-1 is released by gut after eating

GLP-1 agonists increase the amount of insulin released by pancreas

Helps control blood sugar

Aspirin

Pro drug

Salicylic acid and phenol - two acid groups potential GI irritation

Masked as an ester

but reversible reaction forms salicylic acid

prescribe PPI to reduce stomach acid and irritation

Salicylic acid

Too toxic to GI in doses required for analgesia

Aspirin MOA

Inhibits COX-1 (anti-platelet)

Modifies COX-2 (anti-inflammatory)

Blocks thromboxane A2 on platelets

Aspirin uses

Once primary prevention for CV but increased risk of bleeding

Statins better safety profile

Aspirin: ACS, Transient Ischemic attack (stroke), secondary prevention of CV risk

Digoxin

cardiac glycoside

conjugate of steroid aglycone and 3x sugar moiety

Sugar adds a lot of MW (not good for lipinski)

Makes the molecule more active

Increases bioavailability

Sugars are water soluble

most of body is water/ water soluble

better systemic circulation of the drug

Digoxin structure

MW 780 Da

3D structure

Hydrogen at 5 and methyl at 19 are on beta face

Hydroxyl at 14 and methyl at 15 are beta

Creates a present/ croissant shape

Inhibits sodium potassium adenosine triphosphate pump

increase force of contraction

slow the heart