Tricyclic aminopyrimidine histamine H4 receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 21; pp. 6577 - 6581
• Main Authors: SAVALL, Brad M, GOMEZ, Laurent, EDWARDS, James P, CHAVEZ, Frank, CURTIS, Michael, MEDUNA, Steven P, KEARNEY, Aaron, DUNFORD, Paul, COWDEN, Jeffery, THURMOND, Robin L, GRICE, Cheryl
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.11.2011
• Subjects: Animals; Biological and medical sciences; Histamine and antagonists. Allergy; Histamine Antagonists - chemistry; Histamine Antagonists - pharmacology; Medical sciences; Mice; Pharmacology. Drug treatments; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, Histamine; Receptors, Histamine H4; H4 histamine receptor; Fissipedia; Carnivora; Intravenous administration; Rat; Amino pyrimidine; Rodentia; Oral administration; Antagonists; Bioavailability; Tricyclic compound; Histamine; Vertebrata; Mammalia; Structure activity relation; Tricyclic; Animal; Chlorine Organic compounds; Benzofuran; Antagonist; Pharmacokinetics; Chemical synthesis; Histamine H4; Dog
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.08.014

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.