PPAR selectivity

Westergaard, M. etal. Modulation of keratinocyte gene expression and differentiation by PPAR selective ligands tetradecylthioacetic acid, J. Invest Dermatol., 116, 702, 2001. 

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

Zaripheh, S., T. Y. Nara, M. T. Nakamura, and J. W. Erdman, Jr. 2006. Dietary lycopene downregulates carotenoid-15,15 -monooxygenase and PPAR-gamma in selected rat tissues. J Nutr 136(4) 932-938. 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Mechanism of Action Potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) which decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. 

Fig. 1.33 Key polar interactions of PPAR-y-selective agonist rosiglitazone with PPAR-y. The TZD group acts as a carboxylate mimetic.

U., Lindstedt, E.L., Bamberg, K. Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242 ligand selectivity and agonist activation in the PPAR family. Structure (Camb.) 2001, 9, 699-706. 

Figure 7.12 show the results of a validation study. The task was to identify bioisosteric replacements for fragments in known PPAR (peroxisome pro-liferator-activated receptor) ligands. Fibrates are therapeutic agents for the treatment of metabolic disorders and activate PPARoc, a member of the PPAR family.It has been demonstrated that the 2-methyl-propionic acid moiety 7.6 is responsible for the selectivity of fibrates toward PPARa. SQUIRRELnovo suggests bioisosteric replacement for this group. These groups have been patented for action on PPARoc. ... 

The CPCA supenveight plot sho ved that hydrophobic and steric interactions contribute mostly to the discrimination bet veen the three PPAR subtypes. From the supenveight plot, the authors selected three representative probes (DRY, C3 and OH) for the subsequent analysis. 

Although the three remaining subsites of the PPAR LED exhibited less variation than the distal pockets, the CRID/CPCA calculations revealed some scope for selective interactions, in particular with the OH and C3 probes within the linker and head regions. This analysis agreed well with site-directed mutagenesis experiments, as well as the selectivity of known inhibitors. 

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