Discovery of potent and selective PPARα/δ dual antagonists and initial biological studies.

Autor: Jacintho JD; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA. Electronic address: jjacintho@inceptionsci.com., Baccei CS; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Bravo Y; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Broadhead A; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Chen A; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Correa L; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Fischer K; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Laffitte B; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Lee C; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Lorrain DS; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Messmer D; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Prasit P; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Stebbins KJ; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA., Stock NS; Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Feb 01; Vol. 29 (3), pp. 503-508. Date of Electronic Publication: 2018 Dec 21.
DOI: 10.1016/j.bmcl.2018.12.045
Abstrakt: 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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