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

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
(EC50 ∼ 100 nM to 10 μM) that provide distinct
and favorable gene activation profiles for the treatment of diabetes
and obesity.