Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist

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.