Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor superfamily playing a crucial role in the regulation of metabolic homeostasis. As such, the three PPAR isoforms designated α, γ and δ, certainly represent attractive targets for molecules that could be used in diabetes and dyslipidemia.(1) Following the recent indications available in the literature, research is currently addressed to the preparation and characterization of new molecules able to simultaneously activate more PPAR subtypes (PPAR dual agonists and/or pan-agonists), and/or to selectively modulate them (SPPARMs). Recently, we reported the synthesis and biological activity of some chiral carboxylic acid derivatives showing an interesting dual activity towards PPARα and PPARγ with the stereochemistry playing a crucial role in the receptor activation.(2,3) In particular, one of these newly identified PPAR ligands (LT-175, see Figure) has been shown to occupy a branch of the PPARγ ligand-binding domain (LBD), named “diphenyl pocket”, exhibiting the typical profile of partial agonists.(2) The corresponding R enantiomer, instead, is less active fitting another part of the receptor binding pocket. With the aim to evaluate the effects resulting from both interaction modes, we synthesized and tested the dimeric analogs 1-4 characterized by the presence of two carboxylic functions which represent critical contact points for the formation of hydrogen bond networks with the receptor. Preliminary results on PPARα and PPARγ show very interesting activity profiles of these ligands with marked differences depending on the configuration of the two stereogenic centers. The critical influence of stereochemistry on the activity prompted us to accomplish a structural simplification which led to the monocarboxylic derivative 5 containing only one chiral centre. The S enantiomer of this compound (LJ-570) turned out to be the most potent agonist on both receptors. The X-ray structure of the PPARγ/LJ- 570 complex was resolved to investigate the interaction mode and gain structural biology insight into the role played by the carboxylic group and the diphenyl systems present in this ligand.
Design, Synthesis And Biological Evaluation of New Analogs of The Dual PPARα/γ Agonist Lt175 / Laghezza, A.; Pochetti, G.; Piemontese, L.; Sblano, S.; Carrieri, A.; Fracchiolla, G.; Carbonara, G.; Montanari, R.; Lavecchia, Antonio; Tortorella, P.; Loiodice, F.. - (2013), pp. P.IM.05-P.IM.05. (Intervento presentato al convegno XXII National Meeting on Medicinal Chemistry (NMMC 2013) tenutosi a Roma (Italy) nel September 10-13).
Design, Synthesis And Biological Evaluation of New Analogs of The Dual PPARα/γ Agonist Lt175
LAVECCHIA, ANTONIO;
2013
Abstract
Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor superfamily playing a crucial role in the regulation of metabolic homeostasis. As such, the three PPAR isoforms designated α, γ and δ, certainly represent attractive targets for molecules that could be used in diabetes and dyslipidemia.(1) Following the recent indications available in the literature, research is currently addressed to the preparation and characterization of new molecules able to simultaneously activate more PPAR subtypes (PPAR dual agonists and/or pan-agonists), and/or to selectively modulate them (SPPARMs). Recently, we reported the synthesis and biological activity of some chiral carboxylic acid derivatives showing an interesting dual activity towards PPARα and PPARγ with the stereochemistry playing a crucial role in the receptor activation.(2,3) In particular, one of these newly identified PPAR ligands (LT-175, see Figure) has been shown to occupy a branch of the PPARγ ligand-binding domain (LBD), named “diphenyl pocket”, exhibiting the typical profile of partial agonists.(2) The corresponding R enantiomer, instead, is less active fitting another part of the receptor binding pocket. With the aim to evaluate the effects resulting from both interaction modes, we synthesized and tested the dimeric analogs 1-4 characterized by the presence of two carboxylic functions which represent critical contact points for the formation of hydrogen bond networks with the receptor. Preliminary results on PPARα and PPARγ show very interesting activity profiles of these ligands with marked differences depending on the configuration of the two stereogenic centers. The critical influence of stereochemistry on the activity prompted us to accomplish a structural simplification which led to the monocarboxylic derivative 5 containing only one chiral centre. The S enantiomer of this compound (LJ-570) turned out to be the most potent agonist on both receptors. The X-ray structure of the PPARγ/LJ- 570 complex was resolved to investigate the interaction mode and gain structural biology insight into the role played by the carboxylic group and the diphenyl systems present in this ligand.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
