1. Discovery of potent and selective PPARα/δ dual antagonists and initial biological studies
- Author
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Kim Fischer, Bryan Laffitte, Jason D. Jacintho, Christopher Baccei, Catherine Lee, Karin J. Stebbins, Alex R. Broadhead, Davorka Messmer, Lucia Correa, Daniel S. Lorrain, Peppi Prasit, Austin Chen, Nicholas Simon Stock, and Yalda Bravo
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,Antineoplastic Agents ,Pharmacology ,01 natural sciences ,Biochemistry ,Mice ,Structure-Activity Relationship ,Dogs ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,PPAR alpha ,PPAR delta ,Molecular Biology ,Cell Proliferation ,Ovarian Neoplasms ,chemistry.chemical_classification ,Sulfonamides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Antagonist ,Cancer ,Neoplasms, Experimental ,medicine.disease ,Small molecule ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Toxicity ,Molecular Medicine ,Female ,Peroxisome proliferator-activated receptor delta ,Drug Screening Assays, Antitumor ,Antagonism - Abstract
We previously published on the design and synthesis of novel, potent and selective PPARα antagonists suitable for either i.p. or oral in vivo administration for the potential treatment of cancer. Described herein is SAR for a subsequent program, where we set out to identify selective and potent PPARα/δ dual antagonist molecules. Emerging literature indicates that both PPARα and PPARδ antagonism may be helpful in curbing the proliferation of certain types of cancer. This dual antagonism could also be used to study PPARs in other settings. After testing for selective and dual potency, off-target counter screening, metabolic stability, oral bioavailability and associated toxicity, compound 11, the first reported PPARα/δ dual antagonist was chosen for more advanced preclinical evaluation.
- Published
- 2019