2. Academic Validation
  3. Identification of the First PPARα/γ Dual Agonist Able To Bind to Canonical and Alternative Sites of PPARγ and To Inhibit Its Cdk5-Mediated Phosphorylation

Identification of the First PPARα/γ Dual Agonist Able To Bind to Canonical and Alternative Sites of PPARγ and To Inhibit Its Cdk5-Mediated Phosphorylation

  • J Med Chem. 2018 Sep 27;61(18):8282-8298. doi: 10.1021/acs.jmedchem.8b00835.
Antonio Laghezza 1,  Luca Piemontese 1,  Carmen Cerchia 2,  Roberta Montanari 3,  Davide Capelli 3,  Marco Giudici 4,  Maurizio Crestani 4,  Paolo Tortorella 1,  Franck Peiretti 5,  Giorgio Pochetti 3,  Antonio Lavecchia 2,  Fulvio Loiodice 1
Affiliations

Affiliations

  • 1 Dipartimento Farmacia-Scienze del Farmaco , Università degli Studi di Bari "Aldo Moro" , Via Orabona 4 , 70125 Bari , Italy.
  • 2 Dipartimento di Farmacia, "Drug Discovery" Laboratory , Università degli Studi di Napoli "Federico II" , Via D. Montesano 49 , 80131 Napoli , Italy.
  • 3 Istituto di Cristallografia, Consiglio Nazionale delle Ricerche , Montelibretti, 00015 Monterotondo Stazione , Roma , Italy.
  • 4 Dipartimento di Scienze Farmacologiche e Biomolecolari , Università degli Studi di Milano , Via Balzaretti 9 , 20133 Milano , Italy.
  • 5 Aix Marseille Université, INSERM 1263, INRA 1260, C2VN , 13005 Marseille , France.
PMID: 30199253 DOI: 10.1021/acs.jmedchem.8b00835
Abstract

A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand ( S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of ( S)-6 to the canonical site. However, ( S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPARγ Antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, ( S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ at serine 273 that is currently considered the mechanism by which some PPARγ partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPARα/γ dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z