Flashcards in Chapter 3 - Strategies for Drug Discovery and Development Deck (45):
what did Paul Ehrlich do and what did he hypothesise?
He researched into selective cell staining
he hypothesised that molecules can bind to specific receptors
Who is named "father of modern drug discovery"?
antimicrobial discovery by the systematic synthesis and testinf of arsenicals
what was the first effective treatment of syphilis?
who linked aberration in cellular processes and biochemistry?
George Hitchings and Gertrude Elion
what diseases did George Hitchings and Gertrude Elion treat with drugs made by "rational drug design" based on purines and pyrimidines
Leukaemia - thioguanine
gout - allopurinol
malaria - pyrimethamine
What did James Black do?
exploited endogenous molecules to make inhibitors...
adrenaline --> propranolol
beta-blocker for hypertension
histamine --> cimetidine
H2-antagonist for gastric ulcers
What relationship does cost and drug discovery have
exponential increase from years 0-15 reaching an average maximum of ~£1.15 Bn
draw the drug discovery continuum...
idea ---> target identification ---> target validation ---(hit)--> lead discovery ---(lead)--> lead optimisation ---(candidate)--> development ---(IND)--> clinical trials ---(NDA)--> launch ---> clinic
things to consider when starting a drug discovery project?
1. what are the characteristics of successful medicin in the target disease or therapeutic area?
2. who are the patients
3. unmet medical need
4. route of delivery?
5. dosage frequency
characteristics of a medicine
1. engages the desired molecular target
2. achieves desired therapeutic effect
3. drug gets to right site
4. maintains the right concentration for the right duration
5. a suitable formulation containing the drug
6. safe with respect to adverse effects
7. safely eliminated from the body
features of target selection
(identification and validation)
1. cellular and genetic targets
features of lead discovery?
1. structure based
2. assay development
3. high- throughput screening
4. tool and combinatorial synthesis
features of Lead optimisation (medicinal chemistry)
1. library development
2. SAR studies
3. in silico screening
4. chemical synthesis
features of lead optimisation (in vitro studies)
1. drug affinity and selectivity
2. cell disease models
3. mode of action (MOA)
4. lead candidate refinement
features of lead optimisation (in vivo studies)
1. animal models of disease states
2. behavioural studies
3. functional imaging
4. ex-vivo studies
features of clinical trials
1. chemical development
2. clinical trials
what is the objective of target identification in the TARGET SELECTION stage
to identify molecular targets that are involved in the disease progression
what is the objective of target validation in the TARGET SELECTION stage
to prove that manipulation the molecular target can provide therapeutic benefit for patients
what targets are there in the TARGET SELECTION stage
enzymes, GPCRs, ion channels, nuclear hormone receptors, PPIs
what techniques can be used to identify targets in the TARGET SELECTION stage
1. gene mapping
2. seperation and characterisation of proteins
3. data mining
4. computer screening
5. analysis of biological and molecular data
what can be said for observing molecular target of disease with respect to target selection?
1. very easy to design and test assays
2. understanding of mode of action is clear when looking at just the molecular target
3. the relevance to the disease is limited
what can be said for observing target tissue with respect to target selection?
1. assays can be designed and tested but with some difficulty
2. the mode of action can be understood, more complex than molecular mechanism
3. there is some relevance to the disease
what can be said for observing target organ and animal models with respect to target selection?
1. assays are difficult to design and test
2. mode of action is complex and difficult to understand
3. very relevant to the disease
where do we get lead discoveries?
what are leads?
hits refined into a short list of potential chemical starting points based on physicochemical properties
how do we find hits?
exploiting targets known to bind to the target
2. high throughput screening (HTS)
screening large sets of diverse molecules
3. structure based
exploiting knowledge of the 3D structure of the target protein or its protein ligands
what is a HTS?
screening large numbers of compounds in assays with a simple read out yes/no
what were originally used for HTS?
ad hoc assemblies, made for just that purpose... unreliable compounds
what is used for modern HTS?
computational structure/ data visualisation, analysis and management tools
what can be used for structure based design
x-ray and NMR derived 3D structures of proteins
what is fragment based discovery?
structure guided growth of low affinity fragments into drug molecules
what occurs during lead optimisation?
1. iterative cycles of synthesis and testing
2. development of SAR
3. protection of IP (patents)
4. refinement series to meet candidate selection criteria
-on target pharma
-off target pharma
what occurs during the development phase?
1. pre-clinical candidate molecules progressed to "clinical candidate status"
2. chemical development
-grams to kg to tonne
3. good manufacturing route
5. detailed pharmacology
6. acute and short term toxicity
7. geno toxicity
8. clinical trial plans
clinical trials 1?
-safety, pharmacokinetics, pharmacology
clinical trials 2?
-IIa pilot trials to determine safety and efficacy
-IIb larger scale trials to determine safety and efficacy
clinical trials 3?
- large scale to evaluate overall risk-benefit
-leads to NDA
clinical trials 4?
-long term monitoring
why is the pharma industry in a constant state of flux?
1. mergers & takeovers
2. increasing costs
3. cost of R&D
4. external impact (FDA, NICE, government)
6. short patent life
7. managing shareholder/ investor expectations
from target identification to clinical trials, the number of molecules drops from >10,000 to 2-3 then the process may stop. what causes attrition early on in drug discovery?
1. target validity
2. no suitable molecules
3. change in commercial priorities
what scientific reasons lead to attrition in drug discovery?
1. preclinical and clinical efficacy (5 %)
2. preclinical and clinical safety (11 %)
3. bioavailability (5 %)
4. non- clinical toxicology (40 %)
what technical reasons lead to attrition in drug discovery?
1. formulation issues (1 %)
2. patent issues (0.2 %)
what commercial reasons lead to attrition in drug discovery?
1. cost of goods
2. budget/ resource constraints
3. portfolio rationalisation (21 %)
4. potential value
what regulatory reasons lead to attrition in drug discovery?
1. regulatory hurdles
2. regulatory requirements
3. regulatory decisions
how can a pharma company improve productivity?
1. emphasis on reducing attrition
- better predictive models (especially for safety issues)
-better animal models (linking mechanism to disease)
- experimental medicine (innovative ways of demonstrating efficacy in humans)