Advanced Medicinal Chemistry

1
Advanced MedicinalChemistry
Lecture 2
Finding a Lead

• Dr Jeff Stonehouse
• AstraZeneca RD Charnwood

2
The Drug Discovery Process
Target Identification
3 months to 2 years!
HTS
3-4 months
Active-to-Hit (AtH)
3 months
Hit-to-Lead (HtL)
6-9 months
New Lead Optimisation Projects (LO)
2 years
Candidate Drug (CD)
3
Lead Compounds from a Variety of Sources
1. Chance Discovery
2. Natural Products
3. Clinical Observation
4. Natural Ligands 5. Existing Drugs 6. High
Throughput Screening (HTS)
4
Natural Ligands
5
Existing Drugs
Also known as the Me-Too or Me-Better Approach
Issues short duration Multiple side effects and
incompatibility with other drugs
BEWARE Patent Issues!!
36h duration (the weekend pill)
Fewer side effects and incompatibility with other
drugs
6
High Throughput Screening (HTS)
An industrialised process which brings together
validated, tractable targets and chemical
diversity to rapidly identify novel lead
compounds for early phase drug discovery
50-70 of new drug projects originate from a HTS
How?

• validated, tractable targets
• target selection for HTS
• industrialised process
• HTS assay technologies and automation
• chemical diversity
• sample selection for HTS

7
Establishing a HTS
8
Microtitre Plates the HTS test tube
9
Charnwood HTS Technologies 1995-2001

• Screening can utilise numerous
• technologies e.g radioactivity,
• fluorescence, luminescence
• None are universally applicable, each
• with advantages and disadvantages

10
High throughput radioligand binding
assays Scintillation Proximity Assay the first
true homogeneous HTS screening technology
Molecule too far away to activate bead
Bound molecule bead activated light produced
Nothing bound bead not activated, no light
Antibody/receptor
I125
Molecule cannot bind
Suitable for I125, 3H, 33P
11
SPA (Scintillation Proximity Assay)

• First true homogeneous HTS technology
• Allows throughput of 30K compounds/day in 384
  format
• Easy to automate, no significant volume of
  aqueous waste

• BUT
• Radioactive (safety headaches)
• Long read times (gt30min/plate)
• Susceptible to quench artefacts
• Not applicable to all targets

12
FLIPR a high throughput fluorimeter
Fluorescent Imaging Plate Reader Real-time
simultaneous imaging of 96- 384-well
plates Used for HTS Ca2 flux assays and ion
channel screening
13
FLIPR how it works

• Cells loaded with fluorescent dye sensitive to
  Ca2 (fluo-3)
• CCD camera images base of microtitre plate
• Addition of receptor agonist stimulates Ca2
  release, resulting in fluorescence increase
• Whole plate is read simultaneously, allowing
  kinetic analysis
• Functional screen (i.e.whole cell) greater
  relevance than simpler screening methods
• Throughput is 1000x greater than cuvette-based
  fluorimeter assay

14
Establishing a HTS
15
The AstraZeneca Compound Collection
Ca 9 compound overlap
Not a recipe for an optimal screening bank
16
Compound Collection Enhancement

• AZ global initiative to boost screening
  collection
• Target ensure viable Hits from 75 of AZ HTS
• Five-year initial lifespan. Two concurrent themes

17
CCE Structure
HTS Charnwood
HTS AP
Kinase Alderley Park
GPCR Charnwood
60 Scientists Med Chem Bioscience Comp
Chem Informatics
Central Bioscience Cheminformatics
Channel Södertälje
Protease Mölndal
HTS Mölndal
HTS US

• Chemistry deliberately embedded in Research Areas
• Not centralised
• Benefit of Project exposure
• Feeds parallel synthesis skill back into projects

18
CCE Library Chemistry
19
CCE Common Combinatorial Reactions
20
Mechanism
Amide Coupling
Sulphonamide Formation
Reductive Amination