Design and Structural Optimization of Dual FXR/PPARδ Activators

Journal of Medicinal Chemistry
Simone SchierleDaniel Merk

Abstract

Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.

References

Aug 24, 2000·Journal of Medicinal Chemistry·P R MaloneyT M Willson
Aug 9, 2002·Journal of Medicinal Chemistry·Roberto PellicciariTimothy M Willson
Jul 16, 2008·Bioorganic & Medicinal Chemistry Letters·Adwoa Akwabi-AmeyawG Bruce Wisely
Oct 2, 2015·Scientific Reports·Jurema SchmidtDaniel Merk
Feb 9, 2017·Bioorganic & Medicinal Chemistry Letters·Pascal HeitelDaniel Merk
Mar 1, 2017·BMC Medicine·Brent A Neuschwander-Tetri
May 4, 2017·Cell Metabolism·Weiwei FanRonald M Evans
Jul 28, 2017·Journal of Medicinal Chemistry·Daniel FleschDaniel Merk
Apr 5, 2018·Journal of Cheminformatics·Maris LapinsOla Spjuth
Jul 24, 2018·Journal of Medicinal Chemistry·Ewgenij ProschakDaniel Merk
Oct 22, 2018·Cellular and Molecular Life Sciences : CMLS·Fernando BessoneMarcelo G Roma
Dec 31, 2018·Bioorganic & Medicinal Chemistry Letters·Jason D JacinthoNicholas S Stock
Feb 1, 2019·Journal of Medicinal Chemistry·Julius PollingerDaniel Merk
Feb 21, 2019·ACS Medicinal Chemistry Letters·Pascal HeitelDaniel Merk
May 2, 2019·Methods in Molecular Biology·Jan Heering, Daniel Merk
May 8, 2020·Journal of Chemical Information and Modeling·Gabriela Falcón-CanoMiguel Ángel Cabrera-Pérez

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Citations

Apr 16, 2021·ChemMedChem·Simone SchierleDaniel Merk
Jul 28, 2021·Journal of Medicinal Chemistry·Xiangqian LiDayong Shi
Oct 8, 2021·Gut·Michael Trauner, Claudia Daniela Fuchs

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