Lec 7- Drugs and synthetic intermediates Flashcards
1
Q
Where are drugs from- Nature
A
- All antibiotics lead structures
- Anti-cancer drugs
- CNS illict use
- Statin lead structre
- Pain opiates
- Aspirin
2
Q
Where are drugs from- Synthesis
A
- Antibacterial: Ciprofluxacin, F-Gyrase inhibitor, Sulphonamide
- Anti-cancer: Anti-metabolites, alkylating agents
- CNS: amphetamines
- Metabolised: Rosuvastatin
- Pain: Fentanyl
- Inflammation: NSAIDs
- CV: BB, sartanes
- CNS: BZ
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
4
Q
Selected structures
A
- Prontosil = organic dye
- Anti-bacterial- breakthrough sulphone (SO2)amide (NH2)
- Anti-diabetics
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
6
Q
Toxicology- Thalidomide crisis
A
7
Q
Productivity
A
- Thalidomide crisis
- Toxicology
- “Improvement” of regulatory hurdles (constant)
- Increased costs, time
- Less return of investment
- Risk assessment
8
Q
Share the cake- Growth of biopharmaceuticals
A
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
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
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
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%