Lec 10- Drugs and synthetic intermediates (4)

Question 1

Lipid lowering doses range

Answer 1

Question 2

Cholesterol Biosynthesis

Answer 2

• Key enzymatic steps in the biosynthesis of cholesterol are catalyzed by
  
  • HMG-CoA reductase (step a)
  • Squalene epoxidase (Step B)
  • 2,3,-oxidosqualene-sterol cyclase (Step C)
• The biosynthesisi is illustrated in 2 parts
• Statins are all reductase inhibitors

Question 3

Formation of squalene from acetyl-CoA

Conversion of squalene to cholesterol

Answer 3

Question 4

Statins- inhibitors of HMG-CoA reductase

Answer 4

• Mevalonic acid structure resembles the statins

Question 5

Pro-drugs converted into the active form

Answer 5

• On the left is the drug and is metabolised in the body into its active form on the right
• Pravastatin is already in the salt form therefore does not need to be metabolised

Question 6

Classical drug design from lovastatin to rosuvastatin

Answer 6

• Lovastatin, Me group at central decalin ring system
• Mevastatin = Menacolin from fermented red rice, natural product, tranditional herbal medicine
• Lead structure from nature
• Simvastatin, semisynthetic, extra methyl group on side chain, new molecule = Patent
• Blockbuster drug, billions in sales

Question 7

Nautral product to fluvastatin

Answer 7

• Replace central decalin ring system by heterocyclic system
• Which?
• Indol, good synthesise, hydoxy acid must be kept

Question 8

Fluvastatine

Answer 8

• Good concept
• BUT, Not more potent than semi-synthetic simvastatin

Question 9

Fluvastatin to atorvastatin

Answer 9

• Concept: Fuse/Split
• Indol system is fused template
• Split phenyl group off

Question 10

Atorvastatin

Answer 10

• Doesnt raise the HDL

Question 11

Heterocyclic chemistry

Answer 11

Question 12

Cerivastatin

Answer 12

• Ring enlargement fromm 5 member to 6 member ring system
• Central template: Pyrrol => Pyridine
• First super stain
• Withdrawn in most countries
• End of bayer

Question 13

From cerivastatin to rosuvastatin Bioisosteric modification

Answer 13

• From pyridin to pyrimidine ring system
• Concept Classical Bio-isotere
• Extra modification

Question 14

Rosuvastatin

Answer 14

• Methylsulfonamide
• AZ= Crestor
• Half life= 19hrs
• Extra N-Bioisotere
• Best reducatase inhibitor produced, structurally related to toxic cerivastatin
• Side chain: mevalonic acid for molecular recognition
• F-phenyl group
• Isopropyl group (good for blocker, inhibitor
• Extra methyl sulfonamide, pyrimidine in DNA base