Synthesis of new 8(S)-HETE analogs and their biological evaluation as activators of the PPAR nuclear receptors.
Structural modifications around 8-HETE (8-hydroxyeicosatetraenoic acid), a natural agonist of the PPAR (peroxisome proliferator-activated receptor) nuclear receptors have led previously to the identification of a promising analog, the quinoline S 70655. Series of novel quinoline or benzoquinoline derivatives were designed through the modification of this lead. Variations of the nature of the aromatic core and of the side chains were carried out. The SAR studies indicated the high sensitivity of the upper acid chain to modifications as well as the strong effect of the length and size of the lipophilic side chain. They afforded several new promising PPARalpha/gamma dual agonists with a high PPARalpha activity in vitro.
Université de Rennes 1, Laboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Avenue du Général Leclerc, 35042 Rennes - Cedex, France.
Mélanie
M
Liutkus
Frédéric
F
Caijo
Anne-Lise
AL
Girard
Erwan
E
Ayral
Valérie
V
Audinot
Jean A
JA
Boutin
Pierre
P
Renard
Daniel Henri
DH
Caignard
Catherine
C
Dacquet
Alain
A
Ktorza
Paul
P
Mosset
René
R
Grée
D000818:Animals; D019556:COS Cells; D002210:Caprylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D017930:Genes, Reporter; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D024821:Metabolic Syndrome / Q000188:drug therapy; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
D002210:Caprylates; D006893:Hydroxyeicosatetraenoic Acids; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011804:Quinolines; D011993:Recombinant Fusion Proteins; C047628:8-hydroxyeicosatetraenoic acid