Drug Discovery Flashcards
Process of drug development 1) 2) 3) 4) 5) 6) 7)
1) Therapeutic concept
2) Target ID
3) Target validation
4) Screening
5) Lead ID
6) Lead optimisation
7) Drug candidate
Ways to ID target
1) Know disease biology
2) Compare mRNA/protein polymorphism of affected group with normal group
Way to validate target
Find how problem is created and resolved, specifically how a chemical is involved
Experimental way to ID target
In a cell culture, make antisense siRNA to drug target mRNA.
Observe effect of decreased target protein expression.
Purpose of screening
Find a chemical that will interact with target
Two ways that screening can be carried out
1) Screening
2) High-content screening
HIgh-content screening
Fewer compounds tested, more data taken for each sample
Cost of mechanised screening
5 to 50 cents per well
Qualities of lead compound 1) 2) 3) 4) 5) 6)
1) Activity in low mM range
2) Molecular weight <50Da
3) Aqueous solubility, for oral absorption
4) Can permeate through epithelial layers
5) Plasma half-life long enough to have effect in vivo
6) Metabolic stability in liver extract
Lead optimisation
Aqueous solubility, no reactive metabolites (EXCEPT FOR PRODRUGS), not metabolised by polymorphic enzymes, half-life allowing reasonable dose interval (not too frequent doses per day)
Nabilone
CB1 agonist, for pain, nausea-suppression.
Too many contraindications, EG with alcohol
Rimonabant
CB1 agonist
For treatment of hyperlipidaemia
Suppresses appatite
Location of CB1 receptors
CNS
Location of CB2 receptors
PNS
Phase I clinical trials
Test on small number of healthy volunteers.
Testing whether drug is safe or not
