Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis
datasetposted on 2018-03-26, 00:00 authored by Kwangseok Ko, Hye-Jung Kim, Pil-Su Ho, Soon Ok Lee, Ji-Eun Lee, Cho-Rong Min, Yu Chul Kim, Ju-Han Yoon, Eun-Jung Park, Young-Jin Kwon, Jee-Hun Yun, Dong-Oh Yoon, Jung-Sook Kim, Woul-Seong Park, Seung-Su Oh, Yu-Mi Song, Woon-Ki Cho, Kazumi Morikawa, Kyoung-June Lee, Chan-Hee Park
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.
compound 9homology model-guided optimizationcompound 48mouse modelsscreening systemAtopic Dermatitisreceptor familySelective Histamine H 4 Receptor Antagonistnovel classPKH 4R antagonistH 4RADnovel chemotypeanti-inflammation activityhistamine H 4 receptorcompound 48 exhibitsatopic dermatitisH 4R antagonists