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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.

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.

The pressure dependence of the decay of the Ne (2p53p) states excited by an energetic pulsed alpha -particle beam is studied in the pressure range 70-1500 mbar. The 2p53p states are populated either promptly, within a few ns, or by subsequent collisional transfer within the 2p53p states. The decay rates of all the 2p53p states above 300 mbar are linear with the pressure and unaffected by trapping from the 2p53p states as these are depopulated by excimer formation. Below 300 mbar the decay rates are reduced by trapping. No quadratic pressure dependence due to excimer formation is found; the upper limit for the formation rate is estimated as (6*10-7 (ns mbar2)-1. Estimated values for the rates of collisional transfer within and out of the 2p53p configuration are given.