Lecture 56 – drug discovery

Question 1

Choice of a disease

Answer 1

o Commercially driven choose
o Unmet medical need
o Significant market
o Market share opportunity

Question 2

target identification

Answer 2

o Known biology of the disuse
o Result of target finding
o Based on endogenous or plant-derived ligand with known activity
o Omics-based search

Question 3

Target identification using omics

Answer 3

o Gene expression measured by microarray in this study now usually by RT-qPCR or Next generation sequencing
o The potential target gene is not regulated by anti-TNF biologicals, but associates with disease severity, HLA and presence of autoantibody

Question 4

Target evaluation using transgenic told

Answer 4

o Use of GFP
o Drug discovery can also use GFP to determine location of tumour thus target it

Question 5

Target validation

Answer 5

o Transgenics -/- or overexpression
o Natural variants Ob/Ob mouse
o Induced mutations with nitroso-urea
o Targeted approaches
o CRISPR Cas9
o siRNA on cells and in vivo

Question 6

screening

Answer 6

o finding the molecular hit
o target based or cell phenotype

Question 7

From “Molecular hit” to lead compound through medicinal chemistry

Answer 7

o Potent and selective
o Lipinski’s rule of 5 (features of chemical structure eg, ideally mw<500)
o Aqueous solubility (for oral absorption)
o Permeable through epithelial cell layers
o Oral availability in experimental animals
o Metabolic satiability in liver extract
o Sufficient plasma T1/2 to have effect exposure in vivo

Question 8

Lead optimisation

Answer 8

o From lead compound to drug candidate
o Wishlist features
 Aqueous solubility
 No reactive metabolites
 No major active metabolites
 Not metabolised by polymorphic enzymes
 T1/2 to allow “reasonable” dose interval

Question 9

COX2 selectivity – hydrophobic pocket size

Answer 9

o Target driven
o Enzyme cloned
o Product crystalised cf COX-1
o Structure based design

Question 10

COX-2 selective and safety:efficacy ratio

Answer 10

o Lack of divergence in 1st year
o Placebo control
o Dose-related cardiovascular complications

Question 11

Phenotype-based drug discovery

Answer 11

o Know effects:
 Appetite stimulation/anti-nauseant
 Analgesia
 Sedation
 Psych activity

Question 12

Drug discovery to market launch

Answer 12

o Discovery 2-5 years
o Preclinical development 3 years
o Phase I 2 years
o Phase II 2.9 years
o Phase III 3.5 years
o Launch (after NDA filing) 1.8 years
o On average 13.2 years

Question 13

Loss and profit in drug discovery to market journey

Answer 13

o Initially small loss in discovery and preclinical phase
o Major drop during clinical phase
o Large growth over sales, less marketing costs
o Begins to drop back down after patent expiry, generic competition

Question 14

New drug approvals

Answer 14

o Why not?
o The low fruit are picked
o New technologies (omics) not the productivity driver
o The bar is getting higher e.g. safety and selectivity