Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design

OX1
receptor antagonists are of interest to treat, for example,
substance abuse disorders, personality disorders, eating disorders,
or anxiety-related disorders. However, known dual OX1/OX2 receptor
antagonists are not suitable due to their sleep-inducing effects;
therefore, we were interested in identifying a highly OX1 selective
antagonist with a sufficient window to OX2-mediated effects. Herein,
we describe the design of highly selective OX1 receptor antagonists
driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2
receptor antagonist. Moderately selective OX1 antagonists comprising
a [2.2.1]-bicyclic scaffold served as our starting point. Based on
our binding mode hypothesis, we postulated which part of the scaffold
points toward one of the regions where the two binding pockets differ.
Structural changes in this part resulted in a modified core with higher
inherent selectivity compared to the [2.2.1]-bicyclic template. The
structure-based design, synthesis, and hit-to-lead evaluation of this
novel OX1 receptor-selective scaffold are discussed herein.