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Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Apr 12; Vol. 61 (7), pp. 2949-2961. Date of Electronic Publication: 2018 Apr 03. - Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- Animals
Biological Availability
Computer Simulation
Drug Discovery
Drug Evaluation, Preclinical
Female
Histamine Antagonists pharmacokinetics
Inflammation drug therapy
Mice
Mice, Inbred BALB C
Mice, Inbred ICR
Models, Molecular
Molecular Conformation
Molecular Docking Simulation
Pruritus drug therapy
Receptors, Histamine H4 metabolism
Structure-Activity Relationship
Dermatitis, Atopic drug therapy
Histamine Antagonists chemical synthesis
Histamine Antagonists therapeutic use
Receptors, Histamine H4 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29579390
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01855