Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H(1) antagonists

  • Bioorg Med Chem Lett. 2009 May 15;19(10):2766-71. doi: 10.1016/j.bmcl.2009.03.124.
Katsumi Kubota  1 ,  Hirotaka Kurebayashi ,  Hirotaka Miyachi ,  Masanori Tobe ,  Masako Onishi ,  Yoshiaki Isobe
Affiliations
  • 1. Dainippon Sumitomo Phrama. Co. Ltd, Kasagade-naka, Konohana-ku, Osaka-city, Osaka, Japan.
PMID: 19362477 DOI: 10.1016/j.bmcl.2009.03.124
Abstract

A series of phenothiazine carboxylic acid derivatives, having 6-amino-pyrimidine-2,4(1H,3H)-dione moiety via a appropriate linker, were synthesized and evaluated for their affinity toward human histamine H(1) receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice and bioavailability in rats. Finally, promising compounds were examined for their anti-inflammatory potential in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, phenothiazineacetic acid compound 27 showed both histamine H(1)-receptor antagonistic activity and anti-inflammatory activity in vivo model.