title: Discovery of Pyridones As Oral AMPK Direct Activators.
abstract: AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for type 2 diabetes and other metabolic disorders. Here, we will report the discovery of pyrrolopyridone derivatives as AMPK direct activators. We will illustrate the synthesis and structure-activity relationships of the series as well as some pharmacokinetic results. Some compounds exhibited encouraging oral exposure and were evaluated in a mouse diabetic model. Compound 17 showed oral activity at 30 mg/kg on blood glucose.
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sautet
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Catherine-Anne
authors.initials: CA
authors.lastname: Clément
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Toum
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Donche
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Marques
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Rondet
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Pizzonero
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beaufils
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Dudit
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Huet
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Grondin
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Brusq
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Boursier
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Saintillan
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
keywords: AMPK direct activator; P-gp substrate; pyridone; type 2 diabetes