L16 - Lipids (Lecture 3 Part A)

What is the mechanism of action of statins?

Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis that converts HMG-CoA → mevalonate. This decreases hepatic cholesterol synthesis, causing increased hepatic LDL receptor expression and increased removal of LDL from the blood.

What is the rate-limiting step in cholesterol biosynthesis?

Conversion of HMG-CoA → mevalonic acid by HMG-CoA reductase using NADPH.

How do statins affect LDL, HDL, and triglycerides?

LDL ↓ 20–60%; HDL ↑ 5–15%; triglycerides ↓ 7–30%. Their major therapeutic effect is lowering LDL.

What are the major adverse effects of statins?

Transaminitis/hepatotoxicity and myopathy.

What drugs are classified as statins?

Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

Which statin was withdrawn from the market?

Cerivastatin; it was withdrawn in 2001.

What are the Type 1 statins?

Lovastatin, simvastatin, and pravastatin.

What are the Type 2 statins?

Fluvastatin, atorvastatin, rosuvastatin, and pitavastatin.

What structural feature is critical for statin activity?

The 3,5-dihydroxycarboxylate pharmacophore is critical for HMG-CoA reductase inhibition.

Why does the 3,5-dihydroxycarboxylate group allow statins to inhibit HMG-CoA reductase?

It resembles the structure involved in the HMG-CoA → mevalonate reaction and allows strong binding to HMG-CoA reductase.

What stereochemical feature of Type 1 statins is critical for activity?

The absolute configuration/stereochemistry of the two OH groups of the 3,5-dihydroxycarboxylate pharmacophore is critical for activity.

What ring system is characteristic of Type 1 statins?

A decalin-derived fused bicyclic ring system.

What linkage between the active 3,5-dihydroxycarboxylate portion and decalin-derived ring is optimal for Type 1 statins?

A –CH2CH2– linkage.

What effect does an additional methyl group on the butyl side chain have on Type 1 statin activity?

It enhances activity; simvastatin has the additional methyl group and is more active than lovastatin.

How does adding an –OH group to the decalin-derived ring affect a Type 1 statin?

It increases polarity but decreases activity; pravastatin illustrates this relationship.

Which Type 1 statin is the most polar?

Pravastatin because it contains an additional hydroxyl (–OH) group on its decalin-derived ring.

Which Type 1 statins are lactone prodrugs?

Lovastatin and simvastatin.

Is pravastatin a prodrug?

No. Pravastatin is already present in the active open-ring 3,5-dihydroxycarboxylic acid form.

What structural feature identifies lovastatin and simvastatin as prodrugs?

A closed lactone ring rather than the open 3,5-dihydroxycarboxylic acid required for activity.

How are lovastatin and simvastatin activated?

The lactone ring undergoes hydrolysis to produce the open-ring β-hydroxy/3,5-dihydroxycarboxylic acid form that inhibits HMG-CoA reductase.

What type of chemical reaction activates a statin lactone prodrug?

Hydrolysis of the lactone ester opens the ring and forms the active carboxylic acid.

What happens to polarity when a statin lactone is hydrolyzed to its active carboxylic acid?

Polarity increases because the open form contains a carboxylic acid and exposed hydroxyl groups.

How does increased polarity generally affect BBB penetration?

Increased polarity generally decreases passive penetration across the blood-brain barrier.

How does increased lipophilicity generally affect BBB penetration?

Increased lipophilicity generally increases passive BBB penetration.

How do pravastatin and the lactone Type 1 statins compare in lipophilicity?

Pravastatin is more polar/hydrophilic because of its additional OH group, while lovastatin and simvastatin are more lipophilic.

What functional groups should you recognize in lovastatin and simvastatin?

A lactone (cyclic ester), additional ester, alkene, hydroxyl group, alkyl groups, and a fused decalin-derived ring system.

What functional groups should you recognize in pravastatin?

A carboxylic acid, multiple hydroxyl groups, an ester, an alkene, alkyl groups, and a fused decalin-derived ring system.

How can you distinguish a statin prodrug from an active statin acid by structure?

Prodrug: closed lactone ring. Active drug: open 3,5-dihydroxycarboxylic acid containing a free CO2H group.

What happens to lipophilicity when additional OH groups are added to a statin structure?

Lipophilicity decreases and water solubility/polarity generally increases because OH groups can hydrogen bond with water.

How does the carboxylic acid group affect the physicochemical properties of an active statin?

It increases polarity and can ionize at physiological pH, making the active acid form more hydrophilic than the corresponding neutral lactone.

Why can the lactone forms of lovastatin and simvastatin cross lipid membranes more readily than their active acid forms?

The neutral lactone is more lipophilic, whereas opening the lactone produces a more polar/ionizable carboxylic acid.

What is the key Type 1 statin SAR summary?

Activity requires the correctly oriented 3,5-dihydroxycarboxylate; lactones are prodrugs that must be hydrolyzed; correct OH stereochemistry is critical; a –CH2CH2– linkage to the decalin-derived ring is optimal; an extra methyl group can enhance activity; and an additional ring OH increases polarity but can reduce activity.

How do lovastatin and simvastatin differ structurally?

Simvastatin contains an additional methyl group on the butyl side chain compared with lovastatin, which enhances activity.

How does pravastatin differ structurally from lovastatin/simvastatin?

Pravastatin contains an additional OH on the decalin-derived ring and is already in the open active carboxylic acid form rather than a lactone prodrug, making it more polar.

What is the catalytic triad commonly involved in enzymatic ester/lactone hydrolysis?

Serine, histidine, and aspartate (Ser-His-Asp); their microenvironment alters amino-acid pKa values and facilitates catalysis.

How potent is the binding of active lovastatin acid to HMG-CoA reductase according to the lecture?

Very strong binding; KD ≈ 6.5 × 10⁻¹⁰ M.

What is hyperlipidemia?

An excess plasma concentration of cholesterol, cholesterol esters, triglycerides, and/or phospholipids.

Why do lipids require lipoproteins for transport in blood?

Lipids are hydrophobic and therefore require soluble lipoprotein particles for transport through the aqueous bloodstream.

What is the major transport role of LDL?

LDL transports cholesterol and triglycerides from the liver to peripheral tissues and is approximately 22 nm in diameter.

What is the major transport role of HDL?

HDL transports cholesterol and fatty acids from peripheral tissues back toward the liver and is approximately 8–10 nm in diameter.

What is hyperlipoproteinemia?

An increased concentration of soluble lipoproteins in the blood.