ABSTRACT
Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11ß-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11ß-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adipocytes/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Oxazines/chemistry , Adipocytes/cytology , Adipocytes/enzymology , Administration, Oral , Animals , CHO Cells , Cells, Cultured , Cortisone/pharmacology , Cricetinae , Cricetulus , Enzyme Inhibitors/pharmacokinetics , Humans , Macaca fascicularis , Mice , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity Relationship , Tissue DistributionABSTRACT
Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11ß-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
