Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis

The histamine H4
receptor (H4R), a member of the G-protein coupled
receptor family, has been considered as a potential therapeutic target
for treating atopic dermatitis (AD). A large number of H4R antagonists
have been disclosed, but no efficient agents controlling both pruritus
and inflammation in AD have been developed yet. Here, we have discovered
a novel class of orally available H4R antagonists showing strong anti-itching
and anti-inflammation activity as well as excellent selectivity against
off-targets. A pharmacophore-based virtual screening system constructed
in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently
led us to discover pyrido­[2,3-e]­tetrazolo­[1,5-a]­pyrazine analogue 48 as a novel chemotype
of a potent and highly selective H4R antagonist. Importantly, orally
administered compound 48 exhibits remarkable efficacy
on antipruritus and anti-inflammation with a favorable pharmacokinetic
(PK) profile in several mouse models of AD. Thus, these data strongly
suggest that our compound 48 is a promising clinical
candidate for treatment of AD.