Synthesis and Evaluation of PPARδ Agonists That Promote Osteogenesis in a Human Mesenchymal Stem Cell Culture and in a Mouse Model of Human Osteoporosis

We
synthesized a directed library of compounds to explore the structure–activity
relationships of peroxisome proliferator-activated receptor δ
(PPARδ) activation relative to mesenchymal stem cell (MSC) osteogenesis.
Our scaffold used para-substituted cinnamic acids as a polar headgroup,
a heteroatom and heterocycle core connecting units, and substituted
phenyl groups for the lipophilic tail. Compounds were screened for
their ability to increase osteogenesis in MSCs, and the most promising
were examined for subunit specificity using a quantitative PPAR transactivation
assay. Six compounds were selected for in vivo studies in an ovariectomized
mouse model of human postmenopausal osteoporosis. Four compounds improved
bone density in vivo, with two (12d and 31a) having activity comparable to that of GW0742, a well-studied PPARδ-selective
agonist. 31a (2-methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)­phenyl]­thiazole]]­aminocinnamic
acid) had the highest selectivity for PPARδ compared to other
subtypes, its selectivity far exceeding that of GW0742. Our results
confirm that PPARδ is a new drug target for possible treatment
of osteoporosis via in situ manipulation of MSCs.