Lec 7- Drugs and synthetic intermediates

Question 1

Where are drugs from- Nature

Answer 1

1. All antibiotics lead structures
2. Anti-cancer drugs
3. CNS illict use
4. Statin lead structre
5. Pain opiates
6. Aspirin

Question 2

Where are drugs from- Synthesis

Answer 2

1. Antibacterial: Ciprofluxacin, F-Gyrase inhibitor, Sulphonamide
2. Anti-cancer: Anti-metabolites, alkylating agents
3. CNS: amphetamines
4. Metabolised: Rosuvastatin
5. Pain: Fentanyl
6. Inflammation: NSAIDs
7. CV: BB, sartanes
8. CNS: BZ

Question 3

Sulfonamide dynasty

Answer 3

• Prontosil 1932, first antibacterial drug =>
• Sulfanilamide, 1935, active metabolite of protosil -> Other sulfanilamides
• 1949 Acetazolamide- carbonic anhydrase inhibitor
  
  • Other Carbonic anhydrase inhibitor
  • Chlorthiazide 1957, major improvement in diuretics
    
    • Diazoxide, 1961 novel hypotensive drugs
    • Furosemide 1962, first loop diuretic=> other loop diuretics

Question 4

Selected structures

Answer 4

• Prontosil = organic dye
• Anti-bacterial- breakthrough sulphone (SO₂)amide (NH₂)
• Anti-diabetics

Question 5

Sulfon-amides

Answer 5

• Anti-bacterials
• Diuretics
• Anti-diabetics
• 2^nd generation (modification) improved action, PK
• Loss of original bio-activity
• Concept of bio-isosteres
• Concept of classical drug design
• NB- a chemical class urea was systematically varied and evaluated

Question 6

Toxicology- Thalidomide crisis

Answer 6

Question 7

Productivity

Answer 7

• Thalidomide crisis
• Toxicology
• “Improvement” of regulatory hurdles (constant)
• Increased costs, time
• Less return of investment
• Risk assessment

Question 8

Share the cake- Growth of biopharmaceuticals

Answer 8

Question 9

Paclitaxcel (Taxol)

Answer 9

• Generally known as great example of anti-cancer drug from Nature
• Patient life time 20 years. Project start to registration 28 years- too slow

Question 10

Omeprazole vs. Herceptin

Answer 10

• Synthetic: Omeprazole
• Biological: Monoclonal Antibody
• Omeprazole
  
  • Astra, now AZ became global drug company
  • 7 years from phase 1 to registration
  • Billions of revenue, now cheap generics
• Herceptin
  
  • 1^st clinical example of mAb
  • 7 years: phase 1 => registration
  • But, from compound to registration only 10 years
  • Longer life of original (patient) drug
  • Higher return on investment

Question 11

The drug development process

Answer 11

• Discovery phase, medicinal chemistry
• Toxicology, short study, long term study
• Acute toxicology, 4 weeks, 90 days, rodents, dogs, 4 weeks, costs up, early failure
• Role of CRO, contract research organisation
• Phase 1, PK, Cmax, AUC, Healthy volunteers
• Cancer: Phase 1, patients, surrogate endpoint instead of clinical endpoints
• Phase 2, efficacy, patients
• Clinical costs, phase 1, 2-3 million, IND pack 2-3 millions
• New drug application, unmet medicinal need, fast track approval, phase 3

Question 12

Reasons for failure of drug development/termination of NCE

Answer 12

• 1/3 fail due to poor PK, low bioavailability (Cmax, t^1/2, penetration, solubility)
• Why so late? When?- in vitro assay with human liver cells
• Efficacy, CNS drugs worse, anti-infective better
• How useful are animale models of disease?
  
  • Commercial reason- patent expired
  • Animal toxicity: long term, animal model
  • Adverse effects in man 10-16%