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Pharmaceutical Approaches to Antiviral Drug Discovery . Peter S. Dragovich. Pfizer Global Research and Development La Jolla Laboratories. Today's Focus. Drug Discovery/Development Pipeline. Multifaceted, complicated, lengthy process. Pre-clinical Pharmacology. Clinical Pharmacology

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Presentation Transcript
slide1

Pharmaceutical Approaches to Antiviral Drug Discovery

Peter S. Dragovich

Pfizer Global Research and Development

La Jolla Laboratories

slide2

Today's Focus

Drug Discovery/Development Pipeline

  • Multifaceted, complicated, lengthy process

Pre-clinical

Pharmacology

Clinical Pharmacology

& Safety

Pre-clinical Safety

Products

Exploratory Development

Full Development

Discovery

Phase I

Phase II

Phase III

0

15

5

10

Drug

Idea

12 -15 Years

slide3

Product Profiles

Target Identification

Lead generation

Lead optimization

Clinical

Commercial

TA Lead.

Virology

Cell Biol.

Mol. Biol.

Biochem.

HT Screening

HT Chem.

Comp. Chem. Crystallog.

Med. Chem.

Res. Pharm.

PDM

Safety

Process Chem.

Drug Discovery Pipeline

  • Multifaceted, complicated, lengthy process
  • Up to 5 years to complete development transition

Start

3-5 years

Dev.

slide4

Identify differentiation basis for new therapy

    • potency/efficacy
  • dose size/frequency

0.01

0.1

1.0

10.0

Concentration (g/ml)

Lab objectives which address desired profiles

Patient/Product Profiles

  • Identify areas of high unmet medical need
    • Sub-optimal or no existing therapies
  • resistance profile
  • safety/tolerability
slide5

Target Identification

  • Biological entity associated with disease of interest (host or virus origin)
  • Appropriate modulation of target anticipated to impact disease in manner consistent with product profile

Drug Discovery Pipeline

Start

0.5-1 year

Product Profiles

Lead generation

Lead optimization

Dev.

slide6

2. Replication

1. Entry

4. Release

3. Assembly

Target Identification

  • Analyze virus life cycle
  • Identify critical points for intervention (host or virus origin)

Host Cell

Nucleus

slide7

Well defined active (binding) site

Difficult to incorporate all criteria in single target

Target Identification Criteria

  • Activity/function essential for viral replication
    • Proven or inferred through biological experimentation
  • Drugable target (subjective!)
    • Known small molecule inhibitors
  • Historical success against related targets
  • Conservation across virus variants (where applicable)
  • Selectivity vs human proteins
slide8

1

2

3

4

Pr55 gag

p24

p1

p9

p6

p17

8

6

7

5

p24

p1

TF

PR

RT

RN

IN

Pr5160 gag-pol

p17

  • Aspartyl protease
    • Potent renin inhibitor examples
    • Large, lipophilic molecules

Ki <1 nM (human renin)

Target Identification

  • Example: HIV Protease
    • Importance inferred from biology; proven through experimentation1,2

1. Kohl, N. E.; et al. Proc. Natl. Acad. Sci. USA1988, 85, 4686.

2. Kramer, R. A.; et al. Science1986, 231, 1580.

slide9

Identify molecule(s) which interact with chosen target

  • Biological properties attractive/promising but not ideal
  • Amenable to analog production

Drug Discovery Pipeline

Start

0.5-1 year

Product Profiles

Target Identification

Lead generation

Lead optimization

Dev.

slide10

Need reliable and accurate biological assays

  • Routine production of target protein
  • Primary biochemical assay
  • Primary antiviral assay

Lead Generation

  • Secondary assays (counterscreens)
slide11

DNA/RNA template

Synthesized DNA

  • Incorporated into viral DNA by RT enzyme
  • Terminates synthesis (lacks 3'-hydroxyl)

AZT

AZT

Lead Generation

  • Substrate/Ligand analogs
    • Biology or target mechanism must be known
  • Example: HIV RT nucleoside inhibitors

Deoxythymine substrate

slide12

Lead Generation

  • High-throughput screening
    • Large chemical archives (500K to 2MM compounds)
    • Miniaturization = improved cost-effectiveness
slide13

Efavirenz

Lead Generation

  • High-throughput screening
    • Allows for chance discovery of novel inhibitors
  • Example: HIV RT non-nucleoside inhibitors
    • Bind to allosteric site on enzyme surface
    • Disrupt enzyme structure/function
slide14

Prepare/synthesize analogs of leads

  • Improve biological properties
  • Optimized compound(s) suitable for clinical development

Drug Discovery Pipeline

Start

2-3 years

Product Profiles

Target Identification

Lead generation

Lead optimization

Dev.

slide15

Structure-based

design

Combinatorial

Chemistry

Computational

evaluation

Biochemical assays

Antiviral assays

Met./abs./sol. assays

Pharmacokinetics

in vitro / in vivo

Safety assessments

Typical project progression

Development

Candidate

Lead Optimization

  • Iterative process impacted by technology

Idea Generation

Chemical Synthesis

Data Analysis

Biological Evaluation

slide16

Future AV Discovery Needs

  • Continued understanding of patient and physician needs

Product Profiles

Target Identification

Lead generation

Lead optimization

Start

Dev

slide17

Target Identification

Future AV Discovery Needs

  • Good understanding of patient and physician needs
  • Better understanding of virus biology
    • New target opportunities
  • Rapid identification of new viral diseases (SARS)
  • Improved association of viral infection with existing diseases

Product Profiles

Lead generation

Lead optimization

Start

Dev

slide18

Future AV Discovery Needs

  • Improvements in drug discovery/development processes
    • Shorten timelines
    • Reduce attrition

Lead optimization cycle times

Safety predictions

Clinical development times

Products

Exploratory Development

Full Development

Discovery

Phase I

Phase II

Phase III

0

15

5

10

Drug

Idea

12 -15 Years

slide19

Product Profiles

Target Identification

Lead generation

Lead optimization

Summary

  • Antiviral drug discovery
  • Multifaceted, complicated, lengthy process
  • Application will lead to future antiviral therapies which address areas of high unmet medical need

Start

3-5 years

Dev.

slide20

Acknowledgements

Marc Deller

Jay Davies

Amy Patick

Rich Michitsch

Larry Truesdale