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Advanced Medicinal Chemistry

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

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Advanced Medicinal Chemistry

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  1. Advanced MedicinalChemistry Lecture 2: Finding a Lead Dr Jeff Stonehouse AstraZeneca R&D 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. 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)

  4. 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

  5. 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

  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. HT Screen Development validated/ tractable targets target ID human & pathogen genomes chemical space compound selection compound collection Establishing a HTS

  8. 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

  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. 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

  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 (>30min/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 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

  14. HT Screen Development validated/ tractable targets target ID human & pathogen genomes chemical space compound selection compound collection Establishing a HTS

  15. 1994 ASTRA ARCUS ASTRA PAIN CONTROL 1993 1999 The AstraZeneca Compound Collection Ca 9% compound overlap Not a recipe for an optimal screening bank

  16. 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…

  17. 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

  18. 3 most commonly used reactions- • Amide coupling • Reductive amination • Sulphonamide formation CCE – Library Chemistry

  19. Amide Coupling HATU • Sulphonamide Formation NMP • Reductive Amination CCE – Common Combinatorial Reactions

  20. Mechanism Amide Coupling Sulphonamide Formation Reductive Amination

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