Bps Lecture 15 - Drug Discovery

Front 1

Describe 3 important functions of cholesterol.

Back 1

- Vital component of cell membranes

- Precursor to steroid hormones (testerone, cortisol, etc)

- Precursor to bile acids which are crucial to digestion

Front 2

What is cholesterol's relationship with heart disease?

Back 2

Deposition in arteries associated with atherosclerosis and heart disease.

Front 3

Describe the biosynthesis of Mevalonate. (3 steps) What does it ultimately become?

Back 3

1. 3 units of acetate

2. 1 unit HMG-CoA

3. HMG-CoA converted via HMG reductase to mevalonate

Part of cholesterol synthesis.

Hint 3

Front 4

What is the function of HMG-reductase?

Back 4

Mediates the rate-determining step in cholesterol biosynthesis.

(HMG-CoA ----HMG reductase---> Mevalonate)

Hint 4

Front 5

Describe the conversion of mevalonate to famesyl pyrophosphate (C-15). (3 steps)

Back 5

1. Mevalonate converted into C5 unites ("isoprene").

2. Combines via carbo-cation intermediates to C10

3. Add another isoprene (C5) to give C-15.

Hint 5

Front 6

Describe the conversion of C15 unites to cholesterol. (3 steps)

Back 6

1. Two C15 unites are combined to give C30 (squalene)

2. Squalene is oxidized to squalene epoxide.

3. Squalene epoxide is cyclized and additional reactions convert it to cholesterol

Hint 6

Front 7

How does one inhibit cholesterol biosynthesis?

Back 7

Interfere with the rate determining step by inhibiting the enzyme HMG reductase.

This can be done by using a molecule with a similar structure to HMG-Co (which reductase binds to)

Front 8

What is mevastatin?

Back 8

- HMG-CoA reductase inhibitor

- Isolated from penicillium mold

- Japanese scientist Akiro Endo

Hint 8

Front 9

How does mevastatin's structure compare to HMG-CoA

Back 9

- The lactone (ester) ring is closed

Hint 9

Front 10

Why did mevastatin not become a drug?

Back 10

Showed toxicity

Front 11

What part of the mevastatin structure is crucial to its function? Why?

Back 11

Front 12

Describe the structure relationships to: Natural HMG-CoA reductase inhibitors + each other.

Back 12

- All have the open lactone ring (no longer open but cyclized like in HMG)

- All have benzene ring with F attached to N-ring structure

Hint 12

Front 13

What is Lipitor used for? What kind of drug is it? How successful?

Back 13

- Statin

- Used for cholesterol reduction

- Best selling drug in history

Front 14

What is an important adverse side effect of Baycol?

Back 14

Baycol = statin

Rhabdomylolsis -- skeletal muscle wasting + kidney failure

- Relatively rare but caused Baycol to be withdrawn in 2001

Front 15

What is the active ingredient isolated from willow bark? What is it used for?

Back 15

- Salicin

- Pain, fevers, inflammation

Front 16

By 1860, it was realized that salicin could be converted into ________ to result in more effective treatment.

Back 16

Salicylic acid

Note: More side effects!

Front 17

What is ASA?

Back 17

Acetyl Salicylic Acid

More tolerated/effective version of salicylic acid; sold as Aspirin.

Hint 17

Front 18

What are the positive effects of ASA? (4)

Back 18

- Pain relief (analgesic)

- Fever reduction (antipyretic)

- Reduces inflammation

- Reduces blood clotting

Front 19

What is a negative side effect of ASA?

Back 19

Gastric lesions

Front 20

Describe the synthesis of ASA from a phenol.

Back 20

1. Phenol converted to salicylic acid with a base and CO2

2. Salicylic acid converted to ASA thru acetylation.

Hint 20

Front 21

What is ASA's overall mechanism of action?

Back 21

- Inhibits formation of prostaglandins from archadonic acid (polyunsaturated fatty acid)

- Does so by inhibiting COX

Hint 21

Front 22

How is archadonic acid converted to a prostaglandin?

Back 22

1. Reacts with O2 and COX

Hint 22

Front 23

What is the difference between COX-1 and COX-2 enzymes?

Back 23

COX-1: Mediates formation of prostaglandins associated with renewal of stomach/esophagus lining

COX-2: Mediates prostaglandin formation associated with inflammation.

Hint 23

Front 24

What is IC50?

Back 24

Concentration (of a drug) that inhibits 50% of the activity of a substance.

Front 25

Which of the following compounds would be most selective against COX-2?

Back 25

DuP697 -- most resembles shape of COX-2 receptor.

Front 26

Why was Vioxx withdrawn from the market in 2004?

Back 26

- Study showed that long-term use of Vioxx for prevention of colon cancers increased risk of heart attack or stroke by factor of 2

Front 27

Why was Vioxx re-introduced to the market? (2 main)

Back 27

- Benefits outweighed risks for some patients (colon cancer vs heart problems)

- Cardiovascular risks for Vioxx seemed no worse than Ibuprofen

Front 28

Why is Celebrex considered to be 'safer' than Vioxx?

Back 28

- Vioxx more strongly inhibits CO-2

- Speculation: COX-2 does more than just mediate inflammation! May also be present in heart tissues (i.e. cardioprotective function?)