7-Hydroxy-benzopyran-4-one derivatives: a novel pharmacophore of peroxisome proliferator-activated receptor alpha and -gamma (PPARalpha and gamma) dual agonists.
Design, synthesis, and in vitro bioevaluation of a new class of potential dual PPARalpha and gamma agonists discovered through a structure-driven design paradigm are described. The 7-hydroxy-benzopyran-4-one moiety (includes flavones, flavanones, and isoflavones) is the key pharmacophore of these novel molecules, exhibiting similarity to the core structure of both fibrates and thiazolidinediones. New lead PPAR ligands were identified from "natraceuticals" and synthetic analogues. In total, 77 molecules, including chalcones, flavones, flavanones, isoflavones, and pyrazole derivatives, were screened and structure-activity relationship studies of the dual agonists undertaken. Compounds 68, 70, 72, and 76 were identified as novel and potent dual PPARalpha and gamma agonists. These novel molecules may have the potential to be the future leads in PPAR-related disorders, including type II diabetes mellitus and metabolic syndrome.
Matin
Azadeh
A
Faculty of Pharmacy, The University of Sydney, NSW 2006, Sydney, Australia.
Gavande
Navnath
N
Kim
Moon S
MS
Yang
Nancy X
NX
Salam
Noeris K
NK
Hanrahan
Jane R
JR
Roubin
Rebecca H
RH
Hibbs
David E
DE
D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D047493:PPAR alpha; D047495:PPAR gamma