Design, development and evaluation of novel dual PPARδ/PPARγ agonists.

Type 2 diabetes is at epidemic proportions and thus development of novel pharmaceutical therapies for improving insulin sensitivity has become of paramount importance. The objectives of the current study were to develop novel dual PPARγ/δ agonists without the deleterious side effects associated with full PPARγ agonists. Docking simulations of 23 novel compounds within the ligand binding domain of PPARγ/δ were performed using AutoDock Vina which consistently reproduced experimental binding poses from known PPAR agonists. Comparisons were made and described with other docking programs AutoDock and Surflex-Dock (from SYBYL-X). Biological evaluation of compounds was accomplished by transcriptional promoter activity assays, quantitative PCR gene analysis for known PPARγ/δ targets as well as in vitro assays for lipid accumulation and mitochondrial biogenesis verses known PPAR agonists. We found one (compound 9) out of the 23 compounds evaluated, to be the most potent and selective dual PPARγ/δ agonist which did not display the deleterious side effects associated with full PPARγ agonists.

Design of polyamine-based therapeutic agents: new targets and new directions.

Enzymes in the biosynthetic and catabolic polyamine pathway have long been considered targets for drug development, and early drug discovery efforts in the polyamine area focused on the design and development of specific inhibitors of the biosynthetic pathway, or polyamine analogues that specifically bind DNA. More recently, it has become clear that the natural polyamines are involved in numerous known and unknown cellular processes, and disruption of polyamine functions at their effector sites can potentially produce beneficial therapeutic effects. As new targets for polyamine drug discovery continue to evolve, the rational design of polyamine analogues will result in more structurally diverse agents. In addition, the physical linkage of polyamine-like structures to putative drug molecules can have beneficial effects resulting from increases in DNA affinity and selective cellular uptake. The present chapter will summarize recent advances in the development of alkylpolyamine analogues as antitumour agents, and describe subsequent advances that have resulted from incorporating polyamine character into more diverse drug molecules. Specifically, new polyamine analogues, and the role of polyamine fragments in the design of antiparasitic agents, antitumour metal complexes, histone deacetylase inhibitors and lysine-specific demethylase 1 inhibitors, will be described.