CVD MedChem Flashcards
Name the different type of fibrates and their determining structure:
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^
What are the functions of fibrates?
Lower cholesterol and lipid levels
Describe what bile acid sequestrants are:
Chemical drug, doesn’t have a specific biological target
Anion exchange resins
Polymers consisting of cationic backbone
Neutral by presence of conjugated anions
Describe the excretion of bile acid sequestrants:
Large (1million) MW, so not absorbed, not metabolised so excreted as the polymer
Name 2 examples of bile acid sequestrants:
Colestyramine
Colestipol= chloride anions
How do bile acid sequestrants work?
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
What are 2 major bile acids in humans?
Glycoholic acid
Taurocholic acid
Synthetically produced in body from cholesterol
Describe the statins MoA:
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
Why can the statin bind better than the natural substrate?
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
Describe statins as a drug:
Fully selective- specifically on HMG-CoA reductase
Non covalent reversible inhibitor
Name 1st generation statins and describe how they are made?
Focused on SEMI synthetic derivatives
Simvastatin (2-3x more potent that lovastatin)
Pravastatin
Describe the features of simvastatin:
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)
Describe the features of pravastatin:
IC50 44.1nM
No requirement for metabolism as already opened lactone form-prodrug
Synthesised by hydroxylation of devastatin
Better SE profile, though less lipophilic
Name 2nd generation statins and describe how they are made:
Atorvastatin
Fluvastatin
Rosuvastatin- decreased lipopholicity for targeting liver
Synthetic derivatives
Replacement of decalin ring
Hydrophobic region for binding to CoA binding site
Name the IC50 of the second generation statins:
Atorvastatin= 8.2nm
Fluvastatin= 27.6nm
Rosuvastatin= 5.4nm
What is the function of Ezetimibe?
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
Describe the function of plant sterols and stanols:
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
Describe the MoA of plant sterols and stanols:
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
Describe the function of COX:
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
What is the function of PGI2?
A platelet aggregation inhibitor
What is the function of TXA2?
A platelet aggregation inducer
What are 2 roles that COX has in the synthetic pathway?
Endoperoxidase synthase (oxidation and cyclisation)
Peroxidase enzyme (conversion of peroxide to alcohol, reduction)
How is aspirin an effective anti platelet?
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
Name ADP receptor antagonists as an alternative to aspirin:
Thienopyridines:
-clopidogrel
-prasugrel
How do ADP receptor antagonists work?
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
Name and describe other P2Y12 antagonists:
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
Name and describe other alternatives to aspirin:
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)
