CVD treatment med chem

Question 1

what 5 classes of drugs can be used to lower lipids/cholesterol levels

Answer 1

fibrates bile acid sequestrants statins cholesterol absorption inhibitors plant sterols/stanols

Question 2

what is an example of a fibrate

Answer 2

fenofibrate

Question 3

fibrates MOA

Answer 3

pro-drug, acid is the active part, decreases triglyceride levels in the blood

Question 4

fibrates SAR

Answer 4

acid group spacer between acid and rest of molecule chloro group para on ring increases lipophilicity and 1/2 life

Question 5

example of a bile acid sequestrant

Answer 5

cholestyramine

Question 6

how do bile acid sequestrants work

Answer 6

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

Question 7

what is an example of a statin

Answer 7

atorvastatin

Question 8

statin MOA

Answer 8

selective, non-covalent, reversable HMGCoA reductase inhibitor to stop the production of mevalonate - cholesterol precursor

Question 9

how is mevalonate normally synthesised (absence of statins)

Answer 9

1. acetylCoA x 2 (Claisen) -> acetoacetylCoA2. + acetylCoA (aldol) -> HMGCoA3. HMGCoA reductase - mevalonate

Question 10

what are the two steps in mevalonate production by HMGCoA reductase

Answer 10

1. ester reduction carbonyl -> hydroxyl 2. oxidation - CoA removal

Question 11

what happens when statins bind to HMGCoA

Answer 11

lactam ring opens hydrophobic section binds to secondary site not accessed by substrate

Question 12

what is the SAR for a synthetic statin

Answer 12

aromatic N containing ring 5/6 membered must be ortho substituted with 2 methyl groups and a aromatic ring with F

Question 13

what is the SAR for natural statins

Answer 13

decalin ring

Question 14

what is the SAR for intermediate mimic statins

Answer 14

lactone ring in open/closed form OH substitution on ring

Question 15

what is an example of a cholesterol absorption inhibitor

Answer 15

ezetimibe

Question 16

MOA of cholesterol absorption inhibitors

Answer 16

inhibits niemann pick c1 like 1 protein

Question 17

ezetimibe SAR

Answer 17

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

Question 18

how do plant stanols/sterols work

Answer 18

lower blood cholesterol by inhibiting absorption from the gut, competes for micelle formation

Question 19

how does aspirin work as a blood thinner

Answer 19

irreversibly inhibits COX1 by acylating serine at enzyme active site - reduces formation of thromboxane and prostacyclin - decrease in aggregation

Question 20

how does cox work

Answer 20

1. 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

Question 21

which two steps does cox facilitate in the production of prostaglandins

Answer 21

1. endoperoxide synthase - oxidation and cyclisation 2. peroxidase - reduces peroxide to alcohol

Question 22

aspirin MOA

Answer 22

1. 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

Question 23

what is the alternative to aspirin for blood thinning

Answer 23

thienopyridines P2Y12 antagonists

Question 24

what are thienopyridines and how do they work

Answer 24

pro-drugs that antagonise P2Y12, once metabolised thiol forms disulphide bind - irreversible (clopidogrel/prasugrel)

Question 25

what are some examples of other P2Y12 antagonists and why are they different to clopidogrel

Answer 25

ticagrelor - more strongly resembles a nucleoside, not a pro drug, allosteric inhibitors