Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H(1) antagonists.
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.
Dainippon Sumitomo Phrama. Co. Ltd, Kasagade-naka, Konohana-ku, Osaka-city, Osaka, Japan.
Katsumi
K
Kubota
Hirotaka
H
Kurebayashi
Hirotaka
H
Miyachi
Masanori
M
Tobe
Masako
M
Onishi
Yoshiaki
Y
Isobe
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids; D006634:Histamine H1 Antagonists; D010640:Phenothiazines; D011744:Pyrimidinones; D011969:Receptors, Histamine H1