Structure-Based Design and Synthesis of 1,3-Oxazinan-2-one Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1

Abstract

Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-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 11β-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.

Eco‐Efficient Synthesis of Cyclic Carbamates/Dithiocarbonimidates from Cyclic Carbonates/Trithiocarbonate and Aromatic Amines Catalyzed by Ionic Liquid BmimOAc

“…They also have potent activities against Gram‐positive bacterial pathogens including methicillin‐resistant Staphylococcus aureas (MRSA) and vancomycin‐resistant Enterococci (VRE) 1. 3‐Aryl[1,3]oxazinan‐2‐ones have quite recently displayed potency against 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) in humans 2…”

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

“…The use of cerium chloride has been reported to enhance the yields of the addition of Grignard reagents to carbonyl compounds by eliminating undesired side reactions like enolization, reduction, condensation, conjugate addition, and pinacol coupling . Reaction of ( S )‐4‐bromo‐α‐methylbenzylisocyanate (7) with the anion generated from treating this alcohol with lithium hexamethyldisilazane gave a 1:1 mixture of bromooxazinones [ 13 C 6 ]‐(8) and [ 13 C 6 ]‐(9) . The desired bromooxazinone [ 13 C 6 ]‐(9) was easily separated using silica gel chromatography.…”

Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

“…10 mM) and only weak activity against 3b-HSD2 (IC 50 5 4.7 mM). 92 Compound 50 retained efficacy in a human adipocyte assay (IC 50 5 2 nM) but is highly protein bound with less than 1% free drug available in dog, monkey and human plasma. This is consistent with a pronounced (18-fold) reduction in enzyme potency when assayed in the presence of 50% human plasma.…”

“…The compound retained potency against cynomolgus monkey enzyme (IC 50 5 1.0 nM) and subsequently showed efficacy in an in vivo model at a dose of 10 mg/kg, which reduced cortisol production by approximately 85%. 92 …”