title: Effect of oxime ether incorporation in acyl indole derivatives on PPAR subtype selectivity.
abstract: Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a. Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a, less potent as a dual PPARα/γ activator than 20 c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.
authors.affiliation: Laboratoire de Chimie Therapeutique, EA4481, Université Lille-Nord de France, Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Prof. Laguesse, BP83, 59006 Lille, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Le Naour
authors.forename: Veronique
authors.initials: V
authors.lastname: Leclerc
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Valérie
authors.initials: V
authors.lastname: Audinot-Bouchez
authors.forename: Jean-Albert
authors.initials: JA
authors.lastname: Boutin
authors.forename: Michel
authors.initials: M
authors.lastname: Lonchampt
authors.forename: Catherine
authors.initials: C
authors.lastname: Dacquet
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
authors.forename: Pascal
authors.initials: P
authors.lastname: Berthelot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebegue
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects
chemical_list: D007211:Indoles; D010091:Oximes; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates