Thatcher - Statins

Question 1

Statins

Answer 1

First Drug that treat BIOMARKER

NOT DISEASE

PREVENTATIVE

• Target enzymes –> Transition state analogues
  
  • _​_non-covalent binding
  • Hydrophobic interactions
• ME-TOO DRUGS

Question 2

Cholesterol

Answer 2

Fatty Steroid Made in Liver

• Component of biosynthesis of:
  
  • Hormones / Vit D / Bile Acids
• Essential in Structure / Fluidity of membrane

Question 3

LDL Cholesterol

Answer 3

BAD Cholesterol

High LDL –> Atherosclerosis

Question 4

HDL Cholesterol

Answer 4

Good Cholesterol

Carries Cholesterol –> back to LIVER

Question 5

Lipid Related Diseases

Answer 5

• High LDL / Cholesterol Intake Leads to:
  
  • ​Atherogenesis / Atherosclerosis (plaque buildup in blood vessels)
    
    • Heart Attack / CHD
    • Stroke / HIgh BP
    • T2DM
• ​​Can’t do clinical trials on these TAKE TOO MANY YEARS
  
  • ​​Looking at Risk population
  • FDA allows drugs to just REDUCE LOW LDL to approve

Question 6

HMG-CoA Reductase

Answer 6

Rate Limiting Step

of biosynthesis of Cholesterol

• HMG-CoA –> Mevalonate

Question 7

Statin MOA

Answer 7

Inhibit HMG-CoA Reductase

• Lowers production of mevalonate
  
  • ​Reduces cholesterol
  • Immune signaling pathways
  • anti-inflammatory

Question 8

Statin Classification

Answer 8

Chemopreventative Agent

not a disease treatment

• Biomarker = LDL blood test
• Proven to show reduction in risk of Heart Attack / Stroke
• TOTAL OF 7 STATINS APPROVED BY FDA
  
  • ​common MOA
  • differ in PK profiles & lipid-modifying efficacy**​​

Question 9

Type 1 Statins

Lovastatin / Pravastatin / Simvastatin

Answer 9

Indentified as Secondary Metabolites of FUNGI

fermentation of Aspergillus Terreus

Question 10

Type 2 Statins

Atorvastatin / Fluvastatin / Rosuvastatin

Answer 10

Synthetic Compounds

designed to interact w/ HMG-CoA reductase

Question 11

Reversible Competitive Inhibitors

of HmG-CoA Reductase

Answer 11

• Also INDUCE LDL-receptor expression on cell surface
  
  • –> INCREASED extraction of LDL-Cholesterol
    
    • from blood
      
      • –> DECREASED CIRCULATING LDL-C conc

Question 12

Discovery of Lipitor (atorvastatin)

Answer 12

• Triparanol (1959)
  
  • ​first cholesterol lowering agent
    
    • –> last step in cholesterol biosynthesis
    • but severe side effects
• Screen for _microbial produc_t that inhibits cholesterol synthesis
  
  • –> LOVASTATIN
• ​Atorvastatin Approved in 1996
  
  • ​structurally noval HMG-CoA reductase inhibitor
  • Company bought out by PFIZER
    
    • ​Parker davis / Warner Lambert

Question 13

Development of Atorvastatin (lipitor)

Answer 13

Scaffold Hopping

• Lovastatin –> want to remove stereocenters
  
  • –> remove other natural components
• TRANSITION STATE ANALOG
  
  • p-methyl group plays important role in bioactivity
• Halogen –> pyrole ring
  
  • to mimic methyl group & form hydrophobic interaction
    
    • but led to toxicity
• ​​Atorvastatin
  
  • ​formed by replacing CL/BR with EWG

Question 14

Crestor

Rosuvastatin

Answer 14

• Created because we started looking at Statin TRANSPORTERS & Increase in HDL
• Metabolized by CYP2C9 (not 3A4)
• Screening of a series of pyrimidine-substituted heptenoates
  
  • contain sulphonyl moiety
    
    • ​–> lower lipophilicity –> reduced metabolism

Question 15

Statin Metabolism

Answer 15

Mainly CYP3A4

(lovastatin / atorvastatin / simvastatin)

Or 2c9 (fluvastatin)

• rosuvastatin = 2c9/19*
• Phase 2 UGT1A3/2B7*

Question 16

Statin Side Effects

Answer 16

• Muscle (Myopathy)
  
  • ​Cerivastatin was withdrawn
    
    • –> 52 deaths from rhabdomyolysis
      
      • –> renal failure
• Liver
  
  • changes in liver fxn for some people
  • –> increase in enzyme levels –> liver inflammation
• Other
  
  • increase blood sugar - t2dm
  • Neurological side effects (depression / irritability)
  • Headache + N/V

Question 17

Statin Binding Spots

Answer 17

EWG Improves binding affinity

Polar Head group

2- Carbon Linker

Smal Lipophylic alkyl group

Intro of EWG into the 2 & 3 Positions