Chapter 3 - Strategies for Drug Discovery and Development Flashcards Preview

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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"?

Paul Erhlich

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
2. genomics
3. proteonomics
4. bioinformatics


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?

primary assay


what are leads?

hits refined into a short list of potential chemical starting points based on physicochemical properties


how do we find hits?
(3 ways)

1. ligand-based
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?

drug-like properties
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
-disease models


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
4. pharmacy
-physical form
5. detailed pharmacology
6. acute and short term toxicity
7. geno toxicity
8. clinical trial plans


clinical trials 1?

phase I:
-healthy volunteers
-safety, pharmacokinetics, pharmacology


clinical trials 2?

phase II:
-IIa pilot trials to determine safety and efficacy
-IIb larger scale trials to determine safety and efficacy


clinical trials 3?

phase III:
- large scale to evaluate overall risk-benefit
-leads to NDA


clinical trials 4?

Phase IV:
-post launch
-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)
5. implementation
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)


how are business models changing to respond to the challenges facing the pharma industry?

1. reducing internal investment in discovery research
2. increasingly turning to biotech and academia
3. increase outsourcing to CROs
4. more collaborative 'pre-competitive' approaches
5. asset swapping and (re)focussing research portfolio