Synthesis and biological evaluation of new clofibrate analogues as potential PPARalpha agonists.
Clofibrate is a lipid-profile modifying agent belonging to the fibrate class of drugs. Fibrates are known to exhibit their beneficial effects by activating peroxisome proliferator-activated receptor-alpha (PPARalpha) and used in the treatment of dyslipidemia and atherosclerosis and for the prevention of heart failure. Hereby, the preparation of two new sets of clofibrate analogues, ethyl 2-(4-chlorophenoxy)-3-oxoalkanoates and ethyl 2-(4-chlorophenoxy)-3-hydroxyalkanoates is described starting from commercially available 3-oxoalkanoates in fair to good yields. Treatment of 3-oxoalkanoates with SO2Cl2 yielded the corresponding 2-chloro-3-oxoalkanoates, that were then converted into 2-(4-chlorophenoxy)-3-oxoalkanoates by reacting with sodium or caesium 4-chlorophenate. Reduction of the keto group with NaBH4 afforded the corresponding 2-(4-chlorophenoxy)-3-hydroxyalkanoates in very high yields and with variable diastereoselectivity. Biological evaluation of the compounds was performed by a transactivation assay in a transiently transfected monkey kidney fibroblast cell line. The newly synthesised clofibrate analogues failed to show noticeable levels of PPAR activation at concentrations where clofibrate showed an evident activity, suggesting that the structural modifications caused the loss of PPAR activity.
Perrone
Maria Grazia
MG
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via E.Orabona 4, 70125 Bari, Italy.
Santandrea
Ernesto
E
Dell'Uomo
Natalina
N
Giannessi
Fabio
F
Milazzo
Ferdinando Maria
FM
Sciarroni
Anna Floriana
AF
Scilimati
Antonio
A
Tortorella
Vincenzo
V
D000818:Animals; D002460:Cell Line; D002994:Clofibrate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D000882:Haplorhini; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008956:Models, Chemical; D047493:PPAR alpha / Q000819:agonists*; D013237:Stereoisomerism; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism
D004952:Esters; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014157:Transcription Factors; D002994:Clofibrate