New 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors alpha/gamma dual agonists with improved potency and reduced adverse effects on skeletal muscle function.
The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.
Fracchiolla
Giuseppe
G
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, via Orabona 4, 70126 Bari, Italia.
Laghezza
Antonio
A
Piemontese
Luca
L
Tortorella
Paolo
P
Mazza
Fernando
F
Montanari
Roberta
R
Pochetti
Giorgio
G
Lavecchia
Antonio
A
Novellino
Ettore
E
Pierno
Sabata
S
Conte Camerino
Diana
D
Loiodice
Fulvio
F
D000818:Animals; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002995:Clofibric Acid / Q000009:adverse effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004553:Electric Conductivity; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009135:Muscular Diseases / Q000139:chemically induced; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011422:Propionates / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012146:Rest; D013237:Stereoisomerism; D013379:Substrate Specificity
D018118:Chloride Channels; D002712:Chlorides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; D002995:Clofibric Acid