title: Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D.
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.
authors.affiliation: Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. olivier.venier@sanofi-aventis.com
authors.forename: Olivier
authors.initials: O
authors.lastname: Venier
authors.forename: Cécile
authors.initials: C
authors.lastname: Pascal
authors.forename: Alain
authors.initials: A
authors.lastname: Braun
authors.forename: Claudie
authors.initials: C
authors.lastname: Namane
authors.forename: Patrick
authors.initials: P
authors.lastname: Mougenot
authors.forename: Olivier
authors.initials: O
authors.lastname: Crespin
authors.forename: François
authors.initials: F
authors.lastname: Pacquet
authors.forename: Cécile
authors.initials: C
authors.lastname: Mougenot
authors.forename: Catherine
authors.initials: C
authors.lastname: Monseau
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Onofri
authors.forename: Rommel
authors.initials: R
authors.lastname: Dadji-Faïhun
authors.forename: Céline
authors.initials: C
authors.lastname: Leger
authors.forename: Majdi
authors.initials: M
authors.lastname: Ben-Hassine
authors.forename: Thao
authors.initials: T
authors.lastname: Van-Pham
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Ragot
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippo
authors.forename: Géraldine
authors.initials: G
authors.lastname: Farjot
authors.forename: Lionel
authors.initials: L
authors.lastname: Noah
authors.forename: Karima
authors.initials: K
authors.lastname: Maniani
authors.forename: Asma
authors.initials: A
authors.lastname: Boutarfa
authors.forename: Eric
authors.initials: E
authors.lastname: Nicolaï
authors.forename: Etienne
authors.initials: E
authors.lastname: Guillot
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Pruniaux
authors.forename: Stefan
authors.initials: S
authors.lastname: Güssregen
authors.forename: Christian
authors.initials: C
authors.lastname: Engel
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Coutant
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Miguel
authors.forename: Antonio
authors.initials: A
authors.lastname: Castro
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013329:Structure-Activity Relationship
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane