advanced medicinal chemistry l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Advanced Medicinal Chemistry PowerPoint Presentation
Download Presentation
Advanced Medicinal Chemistry

Loading in 2 Seconds...

play fullscreen
1 / 20

Advanced Medicinal Chemistry - PowerPoint PPT Presentation


  • 491 Views
  • Uploaded on

Advanced Medicinal Chemistry. Lecture 2:. Finding a Lead. Dr Jeff Stonehouse AstraZeneca R&D Charnwood. 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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Advanced Medicinal Chemistry' - Jims


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
advanced medicinal chemistry

Advanced MedicinalChemistry

Lecture 2:

Finding a Lead

Dr Jeff Stonehouse

AstraZeneca R&D Charnwood

slide2

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)

slide3

penicillins

taxol

Viagra

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)

slide4

R=H adrenaline

R=Me noradrenaline

Salbutamol GlaxoSmithKline

Formoterol AstraZeneca

Catechol bioisostere (toxicity)

Increased size (selectivity and duration)

Catechol bioisostere (toxicity)

Increased size (selectivity and duration)

Natural Ligands

slide5

Existing Drugs

Pfizer

Viagra

Bayer

Eli Lilly

Levitra

Cialis

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

slide6

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
slide7

HT Screen

Development

validated/

tractable

targets

target

ID

human & pathogen

genomes

chemical

space

compound

selection

compound

collection

Establishing a HTS

slide8

384

96

100-25ml

4.5mm pitch

300-100ml

9mm pitch

1536

For 200K data points:

384LV

10-1ml

2.25mm pitch

25-5ml

4.5mm pitch

9mm

125 x 1536 well plates

500 x 384 well plates

2000 x 96 well plates

Microtitre Plates – the HTS test tube

slide9

Charnwood HTS Technologies; 1995-2001

  • Screening can utilise numerous
  • technologies e.g radioactivity,
  • fluorescence, luminescence
  • None are universally applicable, each
  • with advantages and disadvantages
slide10

I125

Molecule binds

I125

I125

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

slide11

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 (>30min/plate)
  • Susceptible to quench artefacts
  • Not applicable to all targets
slide12

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

slide13

FLIPR – how it works

PC

96/384-Tip Pipettor

Drawer Holding

5 Microplates

6 W Argon Ion Laser

Cooled CCD Camera

  • 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 is1000xgreater than cuvette-based fluorimeter assay
slide14

HT Screen

Development

validated/

tractable

targets

target

ID

human & pathogen

genomes

chemical

space

compound

selection

compound

collection

Establishing a HTS

slide15

1994

ASTRA ARCUS

ASTRA PAIN CONTROL

1993

1999

The AstraZeneca Compound Collection

Ca 9% compound overlap

Not a recipe for an optimal screening bank

slide16

Acquisition

Synthesis

300K from 107 available

Stringent filters

Big Medchem input

Accept IP risks

Nominal 500K over 5 years

Target-class focus

Aligned to Research Areas

Early Bioscience input

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…
slide17

Compound

Management

AP

CCE Structure

HTS

Charnwood

HTS

AP

GPCR

Charnwood

Kinase

Alderley

Park

~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
slide18

3 most commonly used reactions-

    • Amide coupling
    • Reductive amination
    • Sulphonamide formation

CCE – Library Chemistry

slide19

Amide Coupling

HATU

  • Sulphonamide Formation

NMP

  • Reductive Amination

CCE – Common Combinatorial Reactions

slide20

Mechanism

Amide Coupling

Sulphonamide Formation

Reductive Amination