Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

Autor: Lamotte Y; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France. Electronic address: yann.2.lamotte@gsk.com., Faucher N; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Sançon J; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Pineau O; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Sautet S; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Fouchet MH; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Beneton V; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Tousaint JJ; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Saintillan Y; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Ancellin N; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Nicodeme E; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Grillot D; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France., Martres P; Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2014 Feb 15; Vol. 24 (4), pp. 1098-103. Date of Electronic Publication: 2014 Jan 12.
DOI: 10.1016/j.bmcl.2014.01.004
Abstrakt: 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).
(Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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