2. Academic Validation
  3. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists

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

  • Bioorg Med Chem Lett. 2014 Feb 15;24(4):1098-103. doi: 10.1016/j.bmcl.2014.01.004.
Yann Lamotte 1,  Nicolas Faucher 2,  Julien Sançon 2,  Olivier Pineau 2,  Stéphane Sautet 2,  Marie-Hélène Fouchet 2,  Véronique Beneton 2,  Jean-Jacques Tousaint 2,  Yannick Saintillan 2,  Nicolas Ancellin 2,  Edwige Nicodeme 2,  Didier Grillot 2,  Paul Martres 2
Affiliations

Affiliations

  • 1 Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France. Electronic address: yann.2.lamotte@gsk.com.
  • 2 Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France.
PMID: 24462665 DOI: 10.1016/j.bmcl.2014.01.004
Abstract

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).

Keywords

Angiotensin; PPARγ; Peroxisome proliferator-activated receptor; Telmisartan.

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