Pharmaceutical Ways to deal with Antiviral Medication Disclosure.

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Drug Discovery/Development Pipeline. Multifaceted, convoluted, extensive procedure. . . . . . Thought. Drug. 12 - 15 Years. Disclosure. Exploratory Development. Full Development. Stage I. Stage II. Stage III. 0. 15. . . 5. 10. . Pre-clinical Pharmacology. Pre-clinical Safety. Clinical Pharmacology
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Pharmaceutical Approaches to Antiviral Drug Discovery Peter S. Dragovich Pfizer Global Research and Development La Jolla Laboratories

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Today\'s Focus Drug Discovery/Development Pipeline Multifaceted, convoluted, long 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

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Product Profiles Target Identification Lead era Lead enhancement 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, muddled, protracted procedure Up to 5 years to finish advancement move Start 3-5 years Dev.

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Identify separation premise for new treatment strength/adequacy measurements size/recurrence 0.01 0.1 1.0 10.0 Concentration (  g/ml) Lab destinations which address craved profiles Patient/Product Profiles Identify ranges of high unmet restorative need Sub-ideal or no current treatments resistance profile security/passableness

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Target Identification Biological element connected with malady of interest (host or infection cause) Appropriate adjustment of target expected to effect ailment in way steady with item profile Drug Discovery Pipeline Start 0.5-1 year Product Profiles Lead era Lead improvement Dev.

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2. Replication 1. Section 4. Discharge 3. Gathering Target Identification Analyze infection life cycle Identify basic focuses for mediation (host or infection cause) Host Cell Nucleus

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Well characterized dynamic (official) site Difficult to join all criteria in single Target Identification Criteria Activity/capacity fundamental for viral replication Proven or induced through natural experimentation Drugable target (subjective!) Known little atom inhibitors Historical accomplishment against related targets Conservation crosswise over infection variations (where pertinent) Selectivity versus human proteins

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1 2 3 4 Pr55 choke p24 p1 p9 p6 p17 8 6 7 5 p24 p1 TF PR RT RN IN Pr5160 choke pol p17 Aspartyl protease Potent renin inhibitor illustrations Large, lipophilic particles Ki <1 nM (human renin) Target Identification Example: HIV Protease Importance surmised from science; demonstrated through experimentation 1,2 1. Kohl, N. E.; et al. Proc. Natl. Acad. Sci. USA 1988 , 85 , 4686. 2. Kramer, R. An.; et al. Science 1986 , 231 , 1580.

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Identify molecule(s) which connect with picked target Biological properties alluring/promising however not perfect Amenable to simple creation Drug Discovery Pipeline Start 0.5-1 year Product Profiles Target Identification Lead era Lead advancement Dev.

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Need dependable and precise natural tests Routine creation of target protein Primary biochemical measure Primary antiviral test Lead Generation Secondary examines (counterscreens)

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DNA/RNA format Synthesized DNA Incorporated into viral DNA by RT catalyst Terminates combination (needs 3\'- hydroxyl) AZT Lead Generation Substrate/Ligand analogs Biology or target system must be known Example: HIV RT nucleoside inhibitors Deoxythymine substrate

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Lead Generation High-throughput screening Large synthetic documents (500K to 2MM mixes) Miniaturization = enhanced cost-viability

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Efavirenz Lead Generation High-throughput screening Allows for chance disclosure of novel inhibitors Example: HIV RT non-nucleoside inhibitors Bind to allosteric site on chemical surface Disrupt catalyst structure/capacity

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Prepare/blend analogs of leads Improve organic properties Optimized compound(s) reasonable for clinical advancement Drug Discovery Pipeline Start 2-3 years Product Profiles Target Identification Lead era Lead streamlining Dev.

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Structure-based configuration Combinatorial Chemistry Computational assessment Biochemical tests Antiviral measures Met./abs./sol. examines Pharmacokinetics in vitro/in vivo Safety appraisals Typical task movement Development Candidate Lead Optimization Iterative procedure affected by innovation Idea Generation Chemical Synthesis Data Analysis Biological Evaluation

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Future AV Discovery Needs Continued comprehension of patient and doctor needs Product Profiles Target Identification Lead era Lead advancement Start Dev

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Target Identification Future AV Discovery Needs Good comprehension of patient and doctor needs Better comprehension of infection science New target open doors Rapid distinguishing proof of new popular sicknesses (SARS) Improved relationship of viral contamination with existing ailments Product Profiles Lead era Lead streamlining Start Dev

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Future AV Discovery Needs Improvements in medication disclosure/advancement forms Shorten timetables Reduce steady loss Lead enhancement process durations Safety expectations Clinical improvement times Products Exploratory Development Full Development Discovery Phase I Phase II Phase III 0 15 5 10 Drug Idea 12 - 15 Years

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Product Profiles Target Identification Lead era Lead enhancement Summary Antiviral medication revelation Multifaceted, confounded, long process Application will prompt future antiviral treatments which address territories of high unmet medicinal need Start 3-5 years Dev.

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Acknowledgments Marc Deller Jay Davies Amy Patick Rich Michitsch Larry Truesdale

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