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

Starting from 11ß-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 11ß-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.

Pyrrolidine-pyrazole ureas as potent and selective inhibitors of 11ß-hydroxysteroid-dehydrogenase type 1.

A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11ß-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11ß-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.