2. Academic Validation
  3. Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

  • Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018.
Olivier Venier 1,  Cécile Pascal,  Alain Braun,  Claudie Namane,  Patrick Mougenot,  Olivier Crespin,  François Pacquet,  Cécile Mougenot,  Catherine Monseau,  Bénédicte Onofri,  Rommel Dadji-Faïhun,  Céline Leger,  Majdi Ben-Hassine,  Thao Van-Pham,  Jean-Luc Ragot,  Christophe Philippo,  Géraldine Farjot,  Lionel Noah,  Karima Maniani,  Asma Boutarfa,  Eric Nicolaï,  Etienne Guillot,  Marie-Pierre Pruniaux,  Stefan Güssregen,  Christian Engel,  Anne-Laure Coutant,  Beatriz de Miguel,  Antonio Castro
Affiliations

Affiliation

  • 1 Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. olivier.venier@sanofi-aventis.com
PMID: 23478147 DOI: 10.1016/j.bmcl.2013.02.018
Abstract

Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 Enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

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