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
  • 1. Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. [email protected]
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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