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The document describes the discovery of PPAR ligands using parallel solid-phase synthesis of discrete compounds. GW2433 was identified as a potent and selective PPAR delta ligand through screening of a library. Further optimization led to the identification of GW9578, a potent and selective murine PPAR alpha activator. Parallel synthesis allows for rapid examination of structure-activity relationships around compounds of interest and is an effective strategy for lead discovery.
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Brown San Diego99
- 1. The Discovery of PPAR Ligands Using Parallel Synthesis
- 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
- 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. PPAR Profile of Common Fibrates
- 6. PPAR Targeted Library Design Z pharmacophore link X Y Diverse monomers Diverse monomers pharmacophore link X Y
- 8. Resin Loading 25mg of resin = 5mg product (MW=500)
- 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. 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. 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. PPAR Radioligand hPPAR K d = 20 nM Bound (nM) 3 H-GW 2433 (nM) GW 2433 Total Specific Non-specific
- 15. Resin Loading 0.63 mmole/g 100% Loading
- 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. PPAR Screening Data PPAR PPAR GW 9578 PPAR % activation 75-100 50-75 25-50 0-25 X (Alcohols) Y (Isocyanates)
- 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
- 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
Editor's Notes
- 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.