Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases.

Autor:	Sahin C; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada., Magomedova L; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada., Ferreira TAM; Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil., Liu J; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada., Tiefenbach J; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada., Alves PS; Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil., Queiroz FJG; Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil., Oliveira AS; Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil., Bhattacharyya M; Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario M5G 0A3, Canada., Grouleff J; Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario M5G 0A3, Canada., Nogueira PCN; CENAUREMN, Federal University of Ceará, Campus do Pici, Fortaleza, CE 60020-181, Brazil., Silveira ER; CENAUREMN, Federal University of Ceará, Campus do Pici, Fortaleza, CE 60020-181, Brazil., Moreira DC; Faculty of Medicine, University of Brasilia, Brasilia, DF 71910-900, Brazil., Leite JRSA; Faculty of Medicine, University of Brasilia, Brasilia, DF 71910-900, Brazil., Brand GD; Chemistry Institute, University of Brasília, Campus Universitário Darcy Ribeiro, Brasília, DF 70910-900, Brazil., Uehling D; Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario M5G 0A3, Canada., Poda G; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.; Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario M5G 0A3, Canada., Krause H; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada., Cummins CL; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada., Romeiro LAS; Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 1961-1978. Date of Electronic Publication: 2022 Jan 28.
DOI:	10.1021/acs.jmedchem.1c01542
Abstrakt:	Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 ( 23 ) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC 50 ∼ 100 nM to 10 μM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.
Databáze:	MEDLINE
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