CVD treatment med chem Flashcards
what 5 classes of drugs can be used to lower lipids/cholesterol levels
fibrates bile acid sequestrants statins cholesterol absorption inhibitors plant sterols/stanols
what is an example of a fibrate
fenofibrate
fibrates MOA
pro-drug, acid is the active part, decreases triglyceride levels in the blood
fibrates SAR
acid group spacer between acid and rest of molecule chloro group para on ring increases lipophilicity and 1/2 life
example of a bile acid sequestrant
cholestyramine
how do bile acid sequestrants work
chemical drug that are anion exchange resins , anions exchange with bile salts and are excreted with them, cholesterol in absorbed from blood to make more bile acids
what is an example of a statin
atorvastatin
statin MOA
selective, non-covalent, reversable HMGCoA reductase inhibitor to stop the production of mevalonate - cholesterol precursor
how is mevalonate normally synthesised (absence of statins)
- acetylCoA x 2 (Claisen) -> acetoacetylCoA2. + acetylCoA (aldol) -> HMGCoA3. HMGCoA reductase - mevalonate
what are the two steps in mevalonate production by HMGCoA reductase
- ester reduction carbonyl -> hydroxyl 2. oxidation - CoA removal
what happens when statins bind to HMGCoA
lactam ring opens hydrophobic section binds to secondary site not accessed by substrate
what is the SAR for a synthetic statin
aromatic N containing ring 5/6 membered must be ortho substituted with 2 methyl groups and a aromatic ring with F
what is the SAR for natural statins
decalin ring
what is the SAR for intermediate mimic statins
lactone ring in open/closed form OH substitution on ring
what is an example of a cholesterol absorption inhibitor
ezetimibe
MOA of cholesterol absorption inhibitors
inhibits niemann pick c1 like 1 protein
ezetimibe SAR
Azetidinone ringring substituted at S config containing oxygenN must be substituted by ring arylalkyl stereochemistry does not matter - length does mono is better than di substituent
how do plant stanols/sterols work
lower blood cholesterol by inhibiting absorption from the gut, competes for micelle formation
how does aspirin work as a blood thinner
irreversibly inhibits COX1 by acylating serine at enzyme active site - reduces formation of thromboxane and prostacyclin - decrease in aggregation
how does cox work
- removal of hydrogen from arachidonic acid to make hydroxyl (radical)2. oxygen reacts = peroxide w/ radical 3. radical reacts with arachidonic acid double bond 4. cyclisation 5 membered ring5. rearrangement relocates radical 6. conversion to alcohol - PG2 7. rapid conversion to H2
which two steps does cox facilitate in the production of prostaglandins
- endoperoxide synthase - oxidation and cyclisation 2. peroxidase - reduces peroxide to alcohol
aspirin MOA
- H bond with tyrosine 3852. H bond between tyrosine 385 and 348 3. serine hydroxyl on enzyme - transesterification 4. carboxylate anion extracts proton from serine hydroxyl on enzyme 5. oxygen attacks carbonyl on aspirin 6. acetyl-aspirin bond broken, serine is acylated
what is the alternative to aspirin for blood thinning
thienopyridines P2Y12 antagonists
what are thienopyridines and how do they work
pro-drugs that antagonise P2Y12, once metabolised thiol forms disulphide bind - irreversible (clopidogrel/prasugrel)
what are some examples of other P2Y12 antagonists and why are they different to clopidogrel
ticagrelor - more strongly resembles a nucleoside, not a pro drug, allosteric inhibitors
