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 (PPAR alpha/gamma/delta) 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 PPAR alpha and PPAR gamma. 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 similar to 100 nM to 10 mu M) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.