Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed
by combining distinct structural
elements of HTS hit molecules. They were characterized, and several
of them displayed remarkably high affinity for H3 receptors
with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R
activity together with significant in vivo H3 antagonism.
Optimization of the chemotype was initiated with special emphasis
on the elimination of the hERG and muscarinic affinity. Additionally,
ligand-based SAR considerations and molecular docking studies were
performed to predict binding modes of the molecules. The most promising
compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed
antagonist/inverse agonist property in the in vitro functional tests
that was apparent in the rat in vivo dipsogenia test. They were considerably
stable in human and rat liver microsomes and provided significant
in vivo potency in the place recognition and novel object recognition
cognitive paradigms.