Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.
Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France. Electronic address: yann.2.lamotte@gsk.com.
Yann
Y
Lamotte
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Nicolas
N
Faucher
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Julien
J
Sançon
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Olivier
O
Pineau
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Stéphane
S
Sautet
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Marie-Hélène
MH
Fouchet
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Véronique
V
Beneton
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Jean-Jacques
JJ
Tousaint
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Yannick
Y
Saintillan
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Nicolas
N
Ancellin
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Edwige
E
Nicodeme
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Didier
D
Grillot
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Paul
P
Martres
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship
D007191:Indazoles; D047495:PPAR gamma; D000804:Angiotensin II
Angiotensin; PPARγ; Peroxisome proliferator-activated receptor; Telmisartan