Drug Discovery Flashcards
General principle of drug design?
Design on Molecular scale with particular therapeutic outcome
Main approaches
- Small molecule
- Large molecule
- Gene therapy
What is the cost of goods and CNS penetrance in small molecules ?
Low Cost and there is CNS penetrance
Are small molecules validated in MND?
Yes
What are the biological targets of small molecules ??
Enzymes
Kinases
GPCRs
Ion channels
What is the cost of goods and CNS penetrance in Large molecules ??
- High cost
- No penetrance
What is the target of Large molecule drugs ?
- Cytokines
- Cell surface R
- Extracellular proteins
What is the cost of goods and CNS penetrance in Gene therapy ??
- High Cost
- CNS Penetrance
What is the target of gene therapy ??
- Gene Knockdown
- Gene replacement
What is the issue with CNS penetrance ??
BBB restrictions
What type of approach is used in small molecules?
Multidisciplinary
What are the preliminary stages of drug development?
- Target identification
- Hit Identification
- Hit to lead
- Lead optimisation
- Candidate drug Pre nomination
- Clinical development
Target identification
Build a case around particular target disease
Target must be validated – must be significant
Monogenic disorders favoured
- Target must be ‘druggable’
- Must be possible to modulate the target with small molecule drug
Possible Drug targets?
Targets
- Receptors
- Enzyme’s
- Hormones& Factors
- DNA
- Nuclear Receptors
- Ion channels
Issue with drug development ?
Difficult to match up chemistry with biology
Hit identification
- Biochemical screening
- Hit conformation
- Test in more biological relevant assays
- Iterative cycles of making similar compounds, screening those and feeding that information into new syntheses
- Design/test cycles
- Multidisciplinary
Hit to lead
- Additional in vitro tests
- hERG channel assays – cardiac safety screening
- in vivo testing – Distribution, metabolism, pharmacokinetics
- select several families for lead optimisation and further evaluation
Lead optimisation
- Refine activity via further synthesis
- Extensive in vivo testing for PK and efficacy
- Preliminary toxicity in vivo
- Clinical candidate selection
Along side the drug development process…
market analysis formulation, manufacturing scale up, patenting Regulatory – ethics panel
Phase 1
aim- safety, toxicity, does ranging
Endpoint- Pharmacokinetic profiles, Adverse event profile
Nimber- 20-100
Type of study - Single, multiple does with healthy volunteers closely monitored
Success rate- &)%
Phase 2a/2b
Aim- Preliminary Effective ness data Endpoint- Biomarkers study, identify common short term side effects Number- Several hundred Type - Place controlled dose escalation Success- 33%
Phase 3
Aim - Confirmation of effectiveness, evaluation and risk benefit profile
Endpoint- Primary effectiveness
Number - hundreds of thousands
Type- Large placebo controlled
Success - 25-30%
After what phase is approval given ?
Phase 3
Phase 4
Aim- Safety Endpoint- Safety profile in patient population Numbers- Many thousands Type - Comparative Success rate- 20%
Drivers of Drug discovery
Applied research with profit motive Academic drug discovery Open innovation in pharma biotech Research excellent framework Academic entrepreneurship
What is Repurposing?
used already but can it be applied somewhere else \
What is the benefit of repurposing?
- Reduced cost development
- Rapid translation
- Hits likely
What is the disadvantage of repurposing?
- Existing safety data might not support new use
- Unwanted- on target affects – existing use of drug might not be wanted
- Low/no activity at novel targets due to limited chemical diversity
