Lec 7- Drugs and synthetic intermediates Flashcards

1
Q

Where are drugs from- Nature

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

Where are drugs from- Synthesis

A
  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
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3
Q

Sulfonamide dynasty

A
  • 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
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4
Q

Selected structures

A
  • Prontosil = organic dye
  • Anti-bacterial- breakthrough sulphone (SO2)amide (NH2)
  • Anti-diabetics
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5
Q

Sulfon-amides

A
  • Anti-bacterials
  • Diuretics
  • Anti-diabetics
  • 2nd 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
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6
Q

Toxicology- Thalidomide crisis

A
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7
Q

Productivity

A
  • Thalidomide crisis
  • Toxicology
  • “Improvement” of regulatory hurdles (constant)
  • Increased costs, time
  • Less return of investment
  • Risk assessment
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8
Q

Share the cake- Growth of biopharmaceuticals

A
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9
Q

Paclitaxcel (Taxol)

A
  • Generally known as great example of anti-cancer drug from Nature
  • Patient life time 20 years. Project start to registration 28 years- too slow
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10
Q

Omeprazole vs. Herceptin

A
  • 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
    • 1st 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
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11
Q

The drug development process

A
  • 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
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12
Q

Reasons for failure of drug development/termination of NCE

A
  • 1/3 fail due to poor PK, low bioavailability (Cmax, t1/2, 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%
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