Tony James lecture 1

Question 1

Average drug development process

Answer 1

Approx. 12 years, costing approx. $800m

30-40% of all new drugs fail due to poor performance at the animal-human transition (phase 1)

Question 2

Phase 1 clinical trials

Answer 2

Small number (20-100) of healthy volunteers given drug to determine the safe dose/amount of the drug
These tests are also used to determine drug absorption and excretion
Often results in changes to the drug formulation

Question 3

Phase 2 clinical trials

Answer 3

Drug is tested in ~100-300 patients with the illness

Determines efficacy of the drug and further checks safety

Question 4

Phase 3 clinical trials

Answer 4

Involves 1000-3000 patients
Carried out in clinics/hospitals
Patients are closely monitored by doctors to see the drug’s effects/side effects

Question 5

Vioxx

Answer 5

Arthritis painkiller developed by Merck
Removed from the market following a study that linked the drug with heart attacks and strokes in patients that took Vioxx for at least 18 months
Shows that a drug can go through lots of rigorous testing and trials but its ‘true’ side effects only revealed after general use

Question 6

What are the 4 key elements in modern drug discovery?

Answer 6

1. New targets - molecular biology, genomic sciences, biochemistry
2. New molecules - organic chemistry (synthetic small molecules, natural products, peptides/peptidomimetics, combinatorial libraries)
3. Data management
4. High-throughput screening

Question 7

Overview of drug discovery process

Answer 7

Draw

Question 8

Combinatorial chemistry and drug discovery

Answer 8

Draw

Question 9

Define combinatorial chemistry

Answer 9

The use of a small set of chemical building blocks, combined together in different ways using standard chemistries, to create large libraries of medicinally relevant compounds that may be screened for potential new drugs
A technique that allows large numbers of structurally distinct compounds to be synthesised in a time- and resource-effective manner
Used in tandem with high-throughput screening to identify compounds that bind to a therapeutic target and are therefore potential new drugs

Question 10

Types of chemistry used in combinatorial chemistry

Answer 10

Solution phase synthesis
Solid phase synthesis
Split and mix synthesis
High speed parallel synthesis
Scavenging polymers

Question 11

Key feature of combinatorial chemistry

Answer 11

Synthesis is designed such that a range of analogues can be produced using similar reaction conditions, either in the same reaction vessel as mixtures or individually in parallel using semi-automated synthesis

Question 12

Advantage of solid-phase synthesis over solution-phase synthesis

Answer 12

Can add an excess of reagent for solid-phase synthesis because any leftover can be washed away at the end of the reaction
A large excess of reagent would provide purification problems in solution phase synthesis

Question 13

Advantages of solid-phase combinatorial synthesis

Answer 13

Simpler purification - washing and filtration cycles
Can use large excesses of reagents to drive reactions to completion
Can be easily automated for large libraries

Question 14

Disadvantages of solid-phase combinatorial synthesis

Answer 14

Lower reaction rates due to the polymer support (i.e. one reagent is less mobile)
Difficulties in routine analysis of reactions (i.e. can’t NMR/IR without first removing polymer)
Polymer supports can be expensive, especially on a large scale

Question 15

Historic Merrifield resin

Answer 15

Draw

Question 16

Split and mix approach to combinatorial synthesis

Answer 16

Process:

1. Link 3x amino acid to 3x solid support
2. Mix the beads and separate into 3 equal portions
3. React each portion with a different amino acid
4. Mix each product mixture and split into 3 equal portions
5. React each portion with a different amino acid

Produces 27 tripeptides as mixtures in 3 reaction vessels

Question 17

Parallel synthesis approach to combinatorial chemistry

Answer 17

Start with 1 reagent, split between 3 vessels with 3 different reagents
Product of these reactions then split between 3 further vessels
Would give 9 products formed in 9 different reaction vessels

Question 18

Advantages of producing mixtures of compounds

Answer 18

Well-suited process for the linear iterative syntheses of biopolymers

Question 19

Disadvantages of producing mixtures of compounds

Answer 19

Can be difficult to identify hit compounds
False positive results due to synergistic effects - individual compounds may only have very small effects, but appear to be very active when all their effects are added together

Question 20

Advantages of single compound libraries

Answer 20

One compound on one polymer bead

Question 21

Disadvantages of single compound libraries

Answer 21

Logistics of handling/keeping track of 100s/1000s of different compounds

Question 22

Synthetic strategies employed in combinatorial chemistry

Answer 22

1. Iterative strategy

2. Convergent strategy

Question 23

Ideal properties of a compound library

Answer 23

Fast and convergent assembly strategy (i.e. fast reactions)
Good chemical and structural diversity
Good physicochemical properties (e.g. MW < 600)
Versatile synthetic route on solid support
Low manufacturing costs
Bespoke structures (otherwise patent issues)
Targeted and focused library of structures using in silica guidance - random libraries generally have poorer success rates in screening

Question 24

Types of compounds generated by combinatorial chemistry

Answer 24

90% of compounds used for drug discovery
<10% of all compounds produced used as/in: ligands for catalysis, materials science, organic synthesis, molecular sensors, miscellaneous