CVD MedChem

Question 1

Name the different type of fibrates and their determining structure:

Answer 1

Clofibrate- ester prodrug, Cl
Gemfibrozil- with spacer and benzene methyl at both para positions
Fenofibrate- an extended ring structure and acid masked prodrug
Bezafibrate-Cl and triangle- enhanced lipopholicity due to halogen myotis
Ciprofibrate- N^

Question 2

What are the functions of fibrates?

Answer 2

Lower cholesterol and lipid levels

Question 3

Describe what bile acid sequestrants are:

Answer 3

Chemical drug, doesn’t have a specific biological target
Anion exchange resins
Polymers consisting of cationic backbone
Neutral by presence of conjugated anions

Question 4

Describe the excretion of bile acid sequestrants:

Answer 4

Large (1million) MW, so not absorbed, not metabolised so excreted as the polymer

Question 5

Name 2 examples of bile acid sequestrants:

Answer 5

Colestyramine
Colestipol= chloride anions

Question 6

How do bile acid sequestrants work?

Answer 6

In presence of another ion (bile acids in human) exchanged if anion has higher affinity for binding
As patient takes the sequestrant, the anions are exchanged, the polymer is excreted with the bile acid attached to it
Increase excretion means increase synthesis of bile acids from cholesterol so decrease cholesterol

Question 7

What are 2 major bile acids in humans?

Answer 7

Glycoholic acid
Taurocholic acid
Synthetically produced in body from cholesterol

Question 8

Describe the statins MoA:

Answer 8

Statins inhibit the HMG CoA reductase
They can structurally mimic the intermediate- the mevaldic acid hemithioacetal
To do this mimicking, the statins have to be metabolised, the lactone ring in natural product is opened
Opening of lactone ring in vivo- same stereochemistry and functional groups

Question 9

Why can the statin bind better than the natural substrate?

Answer 9

Statin binds 10000x better than the substrate because:
-can mimic intermediate
-binding in 2º binding site (hydrophobic region) which is the binding site for CoA

Question 10

Describe statins as a drug:

Answer 10

Fully selective- specifically on HMG-CoA reductase
Non covalent reversible inhibitor

Question 11

Name 1st generation statins and describe how they are made?

Answer 11

Focused on SEMI synthetic derivatives
Simvastatin (2-3x more potent that lovastatin)
Pravastatin

Question 12

Describe the features of simvastatin:

Answer 12

IC50 11.2nM
Pro drug
Longer t1/2 (2.5x increase)
Synthesised by hydrolysis of lovastatin and hydrolysing natural ester and introducing new ester (re-esterification)

Question 13

Describe the features of pravastatin:

Answer 13

IC50 44.1nM
No requirement for metabolism as already opened lactone form-prodrug
Synthesised by hydroxylation of devastatin
Better SE profile, though less lipophilic

Question 14

Name 2nd generation statins and describe how they are made:

Answer 14

Atorvastatin
Fluvastatin
Rosuvastatin- decreased lipopholicity for targeting liver
Synthetic derivatives
Replacement of decalin ring
Hydrophobic region for binding to CoA binding site

Question 15

Name the IC50 of the second generation statins:

Answer 15

Atorvastatin= 8.2nm
Fluvastatin= 27.6nm
Rosuvastatin= 5.4nm

Question 16

What is the function of Ezetimibe?

Answer 16

Inhibits the absorption of cholesterol at intestinal wall
Related to inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein
Can be used in combination with statins

Question 17

Describe the function of plant sterols and stanols:

Answer 17

Naturally occur in diets
Given as FA esters e.g esters from rapeseed oil
Lower blood cholesterol by inhibiting absorption from gut
Not absorbed themselves
e.g benecol

Question 18

Describe the MoA of plant sterols and stanols:

Answer 18

Cholesterol is absorbed in the gut in the form of mixed micelles (bile salts and cholesterol)
Plant sterols/ stanols compete with cholesterol in micelle formation
Competition for cholesterol transporters

Question 19

Describe the function of COX:

Answer 19

AKA prostaglandin synthase
Membrane embedded protein, majority of structure in cytoplasm
Hydrophobic channel for arachidonic acid into A/S
Allows entry as arachidonic acid is hydrophobic
A/S is a heme moiety

Question 20

What is the function of PGI2?

Answer 20

A platelet aggregation inhibitor

Question 21

What is the function of TXA2?

Answer 21

A platelet aggregation inducer

Question 22

What are 2 roles that COX has in the synthetic pathway?

Answer 22

Endoperoxidase synthase (oxidation and cyclisation)
Peroxidase enzyme (conversion of peroxide to alcohol, reduction)

Question 23

How is aspirin an effective anti platelet?

Answer 23

It irreversibly inhibits COX1
TXA2 an inducer of platelet aggregation will not be synthesised
Platelets are unable to re-synthesise COX1, so synthesis of thromboxanes will be halted for lifetime of platelet
PGI2, an inhibitor of aggregation will not be synthesised, but PGI2 synthesis is more common in endothelial cells which can regenerate COX enzymes but not in platelet
This means even at a very low dose, aspirin can inhibit platelet aggregation

Question 24

Name ADP receptor antagonists as an alternative to aspirin:

Answer 24

Thienopyridines:
-clopidogrel
-prasugrel

Question 25

How do ADP receptor antagonists work?

Answer 25

Antagonises the P2Y12 subtype of the ADP (adenosine diphosphate) receptor
Not active in vivo- undergoes metabolism- prodrugs
Once activated, the thiol forms a disulphide bond with the receptor
Irreversible

Question 26

Name and describe other P2Y12 antagonists:

Answer 26

Cangrelor- IV only prior to surgery, doesn’t require metabolism (lots of P=O, Cl on left)
Ticagrelor- used in combo with aspirin, allosteric inhibitor (OH on left)
Both look like nucleotides

Question 27

Name and describe other alternatives to aspirin:

Answer 27

Selexipag- PCl2 receptor antagonist
Cilostazol- phosphodiesterase inhibitor
Eptifibatide- antagonist of glycoprotein IIB/IIIa receptor, found in snake venom, complexed with fibrinogen, has same arginine glycine glutamic acid (RGD mimic)