Medicinal Chemistry of Statins

Question 1

Statins

Answer 1

• Discovered from fungi
• Mevastatin from Penicillium (lactone ring, hydrolyzed to tetrahedral like in Lovastatin)
• Lovastatin from Monascus ruber and Aspergillus terreus

Question 2

Statin Structure

Answer 2

• Hydrolyzed lactone ring mimics HMG-CoA reaction intermediate (rate-limiting)
• Bicyclic rings then bind to CoA’s binding site
• Statins mimic the tetrahedral intermediate in the HMG-CoA reaction**

Question 3

Potency Order

Answer 3

1. Rosu
2. Ator
3. Sim
4. Lova
5. Prava
6. Pita
7. Fluva

Question 4

Group A Statins

Answer 4

1. Sim
2. Lova
3. Prava

Question 5

Group B Statins

Answer 5

1. Ator
2. Fluva
3. Pita
4. Rosu

Question 6

Group B + Interactions with HMG-CoA Reductase

Answer 6

1. Isopropyl: hydrophobic bonds with Leu, Val, Leu, Ala, Ala
2. Carboxylic Acid - bind to Lys-Lys
3. B-hydroxyl group - binds to Ser-Asp
4. Delta-hydroxyl group - binds to Lys-Asp
5. Para-fluorine - almost ionic bonding with NH2+ group on Arg
6. Sulfonamide - binds with Arg’s NH2+ and Ser’s -OH

Don’t memorize different structures of the statins, just understand their feature and how/where they bind

Question 7

Statin Pharmacore (Group A and B)

Answer 7

• Hydrolyzed lactone ring is analogous to HMG-CoA
• Tetrahedral intermediate
• Stereochemistry 3R,5R (REQUIRED) - the carbons to which the hydroxyls are attached
• 2-carbon bridge after lactone ring (REQUIRED length)

Question 8

Group A Pharmacore Requirements

Answer 8

• Ethyl bridge, no double bonds
• Ester group is critical regardless of stereochemistry
• Decalin ring

Question 9

Group B Pharmacore Requirements

Answer 9

• Ethenyl bridge, double bonded
• Fluorine PARA to central ring (essential)
• Additional binding interactions

Question 10

Group A SAR (fine tuning)

Answer 10

• R1 = hydroxyl for liver specificity and increased hydrophilicity
• R2 = methyl increases activity 2x over hydrogen alone

Question 11

Group B SAR (fine tuning)

Answer 11

• Central ring substitutions that increase activity
• Sulfonamide is the most reactive (rosuvastatin), amide is the second most reaction (atorvastatin)
• Can also be an aromatic ring or alkyl

Question 12

THING TO KNOW FOR EXAM

Answer 12

-Understand rosuvastatin’s binding interactions and be able to apply that to other statins