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  • By far the easiest way to encourage your colleagues to use new technologies is to demonstrate significant advances which are enabled by these new methods. Today, I will be describing some work which shows how the solid-phase synthesis of small pools of compounds has enabled the discovery of PPAR ligands.
  • Brown San Diego99

    1. 1. The Discovery of PPAR Ligands Using Parallel Synthesis
    2. 2. Lead Discovery Strategies Low High High Low Knowledge Base Compound Diversity random screening targeted screening database mining focused libraries small pools combinatorial mixtures discrete compounds
    3. 3. Peroxisome Proliferator-Activated Receptors (PPARs) <ul><li>Orphan members of the nuclear receptor superfamily of ligand-activated transcription factors. </li></ul><ul><li>Drug discovery targets for metabolic and cardiovascular diseases </li></ul>1 liver, kidney, heart PPAR  DNA Ligand 468 1 broadly expressed PPAR  86 70 440 1 adipose, spleen PPAR  83 68 475
    4. 4. PPARs and Metabolic Diseases Subtype PPAR  PPAR  PPAR  Function Triglycerides HDL Glucose ??? Disease CV Risk Factors Type 2 Diabetes ??? Goal: Rapid identification of potent, subtype selective PPAR ligands
    5. 5. PPAR Profile of Common Fibrates
    6. 6. PPAR Targeted Library Design Z pharmacophore link X Y Diverse monomers Diverse monomers pharmacophore link X Y
    7. 7. Retrosynthesis
    8. 8. Resin Loading 25mg of resin = 5mg product (MW=500)
    9. 9. DIC HOBT BH 3 •THF R 2 1 NCO R 2 2 NCO R 2 3 NCO R 2 4 NCO R 2 5 NCO R 2 6 NCO R 2 7 NCO R 2 8 NCO R 1 1 CO 2 H R 1 3 CO 2 H R 1 5 CO 2 H R 1 7 CO 2 H R 1 9 CO 2 H R 1 2 CO 2 H R 1 4 CO 2 H R 1 6 CO 2 H R 1 8 CO 2 H R 1 10 CO 2 H 10% TFA Parallel Synthesis of PPAR Ligands Pip/DMF
    10. 10. PPAR Screening Data A B C D E F G H X (Acids) Y (Isocyanates) plate 1 plate 2 PPAR  PPAR  PPAR  a b c d e f g h i j k l m n o p q r s t % activation 75-100 50-75 25-50 0-25
    11. 11. PPAR  Deconvolution X Y Pharmacophore PPAR  EC 50 (  M) GW 2433 e e f k n n B G B G B G — — — — — — — — 6.3 2.0 — — 1.9 0.16 6.3 0.25 7.9 1.6
    12. 12. PPAR  Radioligand hPPAR  K d = 20 nM Bound (nM) 3 H-GW 2433 (nM) GW 2433 Total Specific Non-specific
    13. 13. Thioisobutyric Acids (TIBA) <ul><li>Sulfur containing headgroup cannot be loaded onto resin using Mukaiyama reagent. </li></ul><ul><li>Borane-sensitive monomers could not be used for monomers containing R 1 . </li></ul><ul><li>Investigate alternative chemistry which would allow a more diverse monomer set to be used at R 1 . </li></ul>
    14. 14. Alternative Synthesis
    15. 15. Resin Loading 0.63 mmole/g 100% Loading
    16. 16. R 1 8 OH R 1 10 OH R 1 6 OH R 1 5 OH R 1 4 OH R 1 3 OH R 1 1 OH R 1 2 OH DIAD PPh 3 HSCH 2 COOH R 2 1 NCO R 2 2 NCO R 2 3 NCO R 2 4 NCO R 2 5 NCO R 2 6 NCO R 2 7 NCO R 2 8 NCO R 1 7 OH R 1 9 OH 10% TFA Parallel Synthesis of PPAR Ligands
    17. 17. PPAR Screening Data PPAR  PPAR  GW 9578 PPAR  % activation 75-100 50-75 25-50 0-25 X (Alcohols) Y (Isocyanates)
    18. 18. PPAR Profile of GW 9578 GW 9578 Fenofibric Acid 300 14 mPPAR EC 50 (  M) 0.005 18 1.5 250    Sel  GW 9578 Fenofibric Acid 1.4 >300 20 10 hPPAR EC 50 (  M) 0.05 30 1 300    Sel  GW 9578 Fenofibric Acid 2.6 >300
    19. 19. Summary <ul><li>Synthesis of libraries of small pools is a powerful method of lead discovery. </li></ul><ul><li>GW2433 was identified as a potent PPAR delta ligand. [ 3 H]-GW2433 can be used in competition-binding assays to rapidly screen for new PPAR ligands with improved subtype selectivities. </li></ul><ul><li>The solid-phase parallel synthesis of discrete compounds is an excellent strategy for examining the SAR surrounding a structure of interest. </li></ul><ul><li>A potent, selective murine PPAR alpha activator was identified (GW 9578). </li></ul>
    20. 20. PPAR Acknowledgements Medicinal Chemistry Peter Brown Adam Fivush Gordon Hodgson Kevin Hurley Dan Sternbach Bill Stuart Nick Tomkinson Tim Willson Tommaso Messeri Radiochemistry Itzela Correa Shimoga Prakash Structural Chemistry Paul Charifson Tom Consler Bruce Wisely Metabolic Diseases Mike Lewis Deborah Winegar William Oliver Joan Wilson Other Collaborators Jim Chapman (Univ. South Carolina) Molecular Endocrinology Steve Kliewer Jürgen Lehmann David Morris Kelli Plunket Tracey Smith-Oliver Laura Wade Molecular Biochemistry Steve Blanchard Lisa Miller Derek Parks Lisa Leesnitzer Analytical Chemistry Doug Minick

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