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.
Liutkus
Mélanie
M
Université de Rennes 1, Laboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Avenue du Général Leclerc, 35042 Rennes - Cedex, France.
Caijo
Frédéric
F
Girard
Anne-Lise
AL
Ayral
Erwan
E
Audinot
Valérie
V
Boutin
Jean A
JA
Renard
Pierre
P
Caignard
Daniel Henri
DH
Dacquet
Catherine
C
Ktorza
Alain
A
Mosset
Paul
P
Grée
René
R
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