Med Chem - Hyperlipidemia Flashcards
Dyslipidemia vs hyperlipidemia
dyslipidemia - blood lipid levels are either too high or too low
hyper - lipid levels too high in blood
the term “hyperlipidemia” means that lipid levels are too high WHERE?
the blood
what is mixed hyperlipidemia
increase in both triglycerides and LDL cholesterol
potential decreases in HDL cholesterol
why is hyperlipidemia bad?
it leads to restricted blood flow – and a risk of coronary artery disease (CAD) or coronary heart disease (CHD)
explain what lipoproteins are
(structure and function)
particles made of lipids (cholesterol, cholesteryl ester, triglycerides) and apolipoproteins
they transport hydrophobic lipids in the blood (blood is hydrophilic – so lipids need lipoprotein as a carrier)
what is the component of a lipoprotein that recognizes the cell receptor and actually delivers the lipids into the cell?
apolipoprotein
name the function of LDL-C vs HDL-C
LDL - carries cholesterol from the liver and to the rest of the body (BAD)
HDL - good cholesterol! helps remove excess cholesterol from the bloodstream by bringing it to the liver for disposal
higher HDL-C levels are associated with….
a lower risk of heart disease :)
high LDL-C levels can lead to….
plaque buildup in the arteries
what is the most common fat in the body
what are they used for?
triglycerides
energy storing
why are high levels of triglycerides bad?
what scenario makes high triglycerides worse?
bc high TG can contribute to atherosclerosis
it’s worse when combined with high LDL levels or low HDL levels
carriers of lipids through the blood
lipoproteins
name the 5 classes of lipoproteins in order of smallest to largest
which has the HIGHEST DENSITY?
smallest - HDL
LDL
IDL
VLDL
largest - chylomicrons
HDL has the highest density
chylomicrons have the lowest density
both chylomicrons and VLDL are ____-rich
triglyceride
which class of lipoproteins is the main carrier of cholesterol in the blood
LDL
explain how high LDL levels cause plaques in the arteries
bc LDL is susceptible to oxidation. when this happens, they are taken up by macrophages, which get “fluffed up” and create plaques
which class of lipoproteins plays an essential role in “reverse cholesterol transport” and what does this mean?
HDL
they bring cholesterol from the body and to the liver for disposal
name of the core structural apoprotein of chylomicrons
what about VLDL?
B48
VLDL - B100
core structural apoprotein of HDL
Apo-AI
____ are highly concentrated stores of metabolic energy
Triglycerides
within adipose cells, where do triglycerides accumulate?
in the cytosol
basic mechanism of statins
HMG-CoA reductase inhibitors
basic mechanism of Fibric Acids
PPARa agonists
full chemical name of “fibric acids”
phenoxyisobutyric aicds
general mechanism of ezetimibe
cholesterol absorption inhibitor
which class of lipid-lowering agents mediates the clearance of LDL cholesterol by activating LDL receptors?
PCSK9 inhibitors (monoclonal antibodies)
general mechanism of niacin as a lipid lowering agent
hydroxycarboxylic acid receptor 2 agonist
general mechanism of bempedoic acid (nexletol) as a lipid lowering agent
ATP citrate lyase (ACLY) inhibitor
What is the name of the intermediate in the conversion from HMG-CoA to mevalonate?
what is important to know about this molecule?
(S)-mevaldyl-CoA
this is the TRANSITION STATE and statins mimic this molecle by both the 3 and 5 OH’s being Beta (pointing up)
TRUE OR FALSE
the conversion of HMG-CoA to mevalonate is a 2 step oxidation reaction
FALSE - 2 step reduction
in the conversion of HMG-CoA to mevalonate, there is inversion of stereochemistry from __ to ___
(3S) to (3R)
**true or false
statins mimic HMG-CoA
FALSE - they mimic the transition state - mevaldyl-Coa
1 OH is beta and the other is alpha
what is the only natural 1st generation statin
mevastatin
*Is the stereochemmistry of mevaldyl-CoA at the 3 position still S? or has it changed to R already?
still S
only changes to R when the final product is formed
*for which does stereochemistry matter more - 1st generation or 2nd generation statins?
1st generation!!!!!
the OH groups on dihydroxyheptaonic acid (or its lactone ring if a prodrug) MUST be 3R, 5R in order to mimic the hydroxy groups of S)-Mevadyl-CoA
true or false
pravastatin is a LESS active metabolite of mevastatin
true
name the 4 1st gen statins
mevastatin
lovastatin
simvastatin
pravastatin
true or false
all of the 1st gen statins are prodrugs
FALSE - all except pravastatin
***CRITICAL pharmacophore for all statins
3R, 5R-dihydroxyheptanoic acid
this configuration allows both of the 3 and 5 OH’s to be BETA!! mimicking (S)-mevaldyl-CoA
what is the general change from 1st gen to 2nd gen statin
what was important to keep the same?
VERY important for the 3, 5-dihydroxyheptanoic acid to remain the same (stereochemistry DOES NOT MATTER!!!! AS LONG AS OH POINT SAME WAY AS MEVADYL)
however, the didehydrodecalin ring was changed to other hydrophobic groups – ie - indole, pyrrole, quinoline, pyrrole, etc
TRUE OR FALSE
2nd gen statins are more lipophilic than 1st gen statins
true
true or false
2nd gen statins have more chiral centers than 1st gen
FALSE
2nd gen statins have less chiral centers
**the 2 OH’s which are critical for statin activity undergo what kind of binding?
hydrogen bonding
*how many different regions of the enzyme (HMG-CoA reductase) do statins bind to?
name the interactions
4 different regions
the 2 OH’s undergo H-bonding
COO- undergoes ionic interaction with (+) charged aa
hydrophobic interaction protrudes OUTSIDE of the enzyme-ligand binding pocket
name the only 2 hydrophilic statins
how are they hydrophilic?
pravastatin and rosuvastatin
pravastatin already has lactone ring hydrolyzed. (not a prodrug)
rosuvastatin has a sulfonamide group at the bottom, making it hydrophilic
true or false
pravastatin and atorvastatin are the only hydrophilic statins. the rest are lipophilic
FALSE
pravastatin and rosuvastatin
*which are more of a concern and why - hydrophilic or lipophilic statins?
lipophilic statins are more of a concern bc they are NOT hepato-selective. they can passively diffuse through cell membranes of other tissues besides the liver
hydrophilic statins, however, are hepatoselective. they need carrier-mediated uptake into the liver
true or false
lipophilic statins are hepato-selective
FALSE - hydrophilic are
one of the most ____ statins (_____), was withdrawn from the market bc it showed severe myopathy
lipophilic/potent
Cerivastatin
*name 3 statins metabolized by CYP3A4
SAL
simvastatin
atorvastatin
lovastatin
*what CYP metabolizes fluvastatin
2C9
*what CYP metabolizes pravastatin and rosuvastatin
NONE - mostly excreted unchanged (hydrophilic)
fibric acid drugs are derivatives of….
phenoxyisobutyric acid
name 3 fibrates
which are prodrugs?
fenofibrate
clofibrate
gemfibrozil
fenofibrate and clofibrate are prodrugs (their COOH is esterified!)
which functional group of fibrates is CRITICAL for it to be active
COO- (anion)
**explain the MOA of fibrates
they activate PPAR-a
the activated PPAR-a forms a heterodimer with RXR
this allows the transcription of target genes
*what does PPAR-a activation by fibrates do to LDL particle size?
increases LDL particle size. larger LDL is better because it is not susceptible to oxidation and being taken up by macrophages to form a plaque
*what does PPAR-a activation by fibrates do to HDL synthesis
increased HDL synthesis
**true or false
fibrates, through activating PPAR-a, decrease reverse cholesterol transport
FALSE
increase reverse cholesterol transport
meaning that more cholesterol from the blood is delivered to the liver to be excreted in feces
what kind of receptor is PPARa
a nuclear receptor
**HOW do fibrates decrease triglycerides
by increasing LPL (lipoprotein lipase) expression
this enzyme hydrolyzes triglycerides into free fatty acids
in turn, these free fatty acids undergo increased B-oxidation – and thus TG synthesis is also inhibited
*true or false
fibrates decrease inflammation
true
*true or false
larger LDL size is better
TRUE - resistant to oxidation
considered anti-atherogenic
**through which bonds do fibrates bind to PPAR-a
ALL 4 are hydrogen bonds
this is why the free COO- needs to be exposed for activity
**explain the metabolism of fenofibrate
fenofibrate is a PRODRUG
therefore, the ester is hydrolyzed to its active form
this COOH now exposed, will eventually undergo glucuronic acid conjugation
which undergoes more extensive metabolism and why - fenofibrate or gemfibrozil?
gemfibrozil bc its more lipophilic
**explain the metabolism of gemfibrozil
are the metabolites active or inactive
first, hydroxylation through CYP3A4
next, alcohol dehydrogenase converts the OH to the aldehyde version, and then aldehyde dehydrogenase converts to the Carboxylic acid metabolite
ALL the metabolites are inactive
**explain the MOA of ezetimibe
NPC1L1 antagonist
NPC1L1 is a protein on the wall of the intestine which absorbs dietary cholesterol. thus, ezetimibe inhibiting this protein inhibits the absorption of dietary cholesterol
*explain the metabolism of ezetimibe (state both the major and minor pathways)
major - phenolic OH is glucuronidated. this metabolite is ACTIVE and undergoes repeated enterohepatic recirculation giving a LONG DURATION OF ACTION
minor - aliphatic OH is oxidized to an INACTIVE ketone
(major route is active, minor route is inactive)
in which organ are bile acids and bile salts synthesized??
where are they stored?
in the liver
stored in the gallbladder
*explain the function of bile acids and bile salts
they emulsify dietary lipids and fat soluble vitamins – which helps their absorption through the intestine
*what is the RATE DETERMINING ENZYME in the conversion of cholesterol to bile acids and then to bile salts
7a-hydroxylase
**name the 2 steps in the conversion of cholesterol to bile acid and then to bile salt
cholesterol -> bile acid – C-12 hydroxylation and side chain oxidation by rate limiting enzyme (7a-hydroxylase)
bile acid -> bile salt - conjugation with glycine
***explain how the negative feedback mechanism works in terms of bile salts
when bile salt (glycocholate) is produced, it goes back to the liver and “tells” the liver not to convert any more cholesterol into bile acid (bc there’s enough!)
