Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D
Venier, O., Pascal, C., Braun, A., Namane, C., Mougenot, P., Crespin, O., Pacquet, F., Mougenot, C., Monseau, C., Onofri, B., Dadji-Faihun, R., Leger, C., Ben-Hassine, M., Van-Pham, T., Ragot, J.L., Philippo, C., Farjot, G., Noah, L., Maniani, K., Boutarfa, A., Nicolai, E., Guillot, E., Pruniaux, M.P., Gussregen, S., Engel, C., Coutant, A.L., de Miguel, B., Castro, A.(2013) Bioorg Med Chem Lett 23: 2414-2421
- PubMed: 23478147 
- DOI: https://doi.org/10.1016/j.bmcl.2013.02.018
- Primary Citation of Related Structures:  
4HX5 - PubMed Abstract: 
Starting from 11¦Â-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 11¦Â-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.
Organizational Affiliation: 
Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. olivier.venier@sanofi-aventis.com