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1.
Diab Vasc Dis Res ; 11(6): 440-7, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25212694

ABSTRACT

We report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.


Subject(s)
Chalcones/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Propionates/therapeutic use , Animals , Blood Glucose/drug effects , Chalcones/pharmacology , Diabetes Mellitus, Experimental/blood , Drug Evaluation, Preclinical , Lipids/blood , Male , Mice , PPAR alpha/agonists , PPAR delta/agonists , Propionates/pharmacology , Random Allocation
2.
J Biomol Screen ; 19(3): 399-406, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23896689

ABSTRACT

Plants represent a tremendous structural diversity of natural compounds that bind to many different human disease targets and are potentially useful as starting points for medicinal chemistry programs. This resource is, however, still underexploited due to technical difficulties with the identification of minute quantities of active ingredients in complex mixtures of structurally diverse compounds upon raw phytomass extraction. In this work, we describe the successful identification of a novel class of potent RAR-related orphan receptor alpha (RORα or nuclear receptor NR1F1) agonists from a library of 12,000 plant extract fractions by using an optimized, robust high-throughput cell-free screening method, as well as an innovative hit compound identification procedure through further extract deconvolution and subsequent structural elucidation of the active natural compound(s). In particular, we demonstrate that neoruscogenin, a member of the steroidal sapogenin family, is a potent and high-affinity RORα agonist, as shown by its activity in RORα reporter assays and from its effect on RORα target gene expression in vitro and in vivo. Neoruscogenin represents a universal pharmacological tool for RORα research due to its specific selectivity profile versus other nuclear receptors, its excellent microsomal stability, good bioavailability, and significant peripheral exposure in mouse.


Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 1/agonists , Spirostans/pharmacology , Biological Products/pharmacology , Drug Discovery , High-Throughput Screening Assays , Plant Extracts/chemistry , Plant Extracts/pharmacology , Reproducibility of Results , Small Molecule Libraries
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