Synthesis and biological evaluation of regulators of peroxisome proliferator-activated receptors
Appears in the following Collection
- Farmasøytisk institutt 
AbstractThe powerful and selective PPARδ agonist, GW 501516 (18), was used as a lead compound for new compounds with potential agonistic effects. The compounds were biologically evaluated using the oleic acid oxidation assay and the luciferase-based transient transfection assay.
Modification of the lead compound by replacing the thiazole ring with a 1,4-disubstituted 1,2,3-triazole ring and by conducting structure-activity relationship (SAR) studies led to three series of new agonists. Triazole 52e of the first series increased the oxidation of oleic acid exhibiting an EC50-value of 0.85 nM. Compound 52e showed dual PPARα/δ agonistic effects at 10 μM concentration. Acid 55a of the second series was 600 times less potent than the lead compound GW 501516 (18) regarding to the oxidation of oleic acid, but it proved to be a medium effective PPARα agonist at 10 μM concentration. Compounds 69a-69c of the third series induced oxidation of oleic acid with nanomolar potencies and exhibited dual PPARα/δ agonistic effects at 10 μM concentration.
Further SAR studies led to compound 62e with high potency both in the oleic acid oxidation assay and the luciferase-based transient transfection assay. Moreover, the thiazole 62e showed a high selectivity towards PPARδ. The influence of a fluorine atom on the acidic moiety of our most potent compounds was investigated. This modification led to three new dual PPARα/δ at 10 μM concentration.
Finally, we prepared and biologically evaluated using the oleic acid oxidation assay two known PPARδ antagonists, GSK 0660 (42) and GSK 3787 (43), and a potentially new PPARδ antagonist (103). Compound 103 showed initial promising biological effects.
List of papers. Papers I, III and IV are removed from the thesis due to copyright restrictions.
Paper I Synthesis and dual PPARa/d agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516. Calin C. Ciocoiu, Nataša Nikolic, Huyen Hoa Nguyen, G. Hege Thoresen, Arne J. Aasen, Trond Vidar Hansen. European Journal of Medicinal Chemistry 2010, 45, 3047-3055. doi:10.1016/j.ejmech.2010.03.035
Paper II Synthesis, biological evaluation and molecular modeling of analogues of GW 501516. Calin C. Ciocoiu, Aina W. Ravna, Ingebrigt Sylte, Trond Vidar Hansen. Accepted: August 20, 2010. Archiv der Pharmazie 2010, 343(11-12), 612–624. doi:10.1002/ardp.201000189
Paper III Synthesis and biological evaluation of fluorine analogs of GW 501516. Calin C. Ciocoiu, Aina W. Ravna, Ingebrigt Sylte, Arild C. Rustan, Trond Vidar Hansen. Bioorganic and Medicinal Chemistry. Accepted not published.
Paper IV Synthesis, molecular modeling and initial biological evaluation of CC 618: a PPARd antagonist. Calin C. Ciocoiu, Aina W. Ravna, Ingebrigt Sylte, G. Hege Thoresen, Trond Vidar Hansen Manuscript, submittet not published.