Synthesis and structure-activity relationship of tricyclic carboxylic acids as novel anti-histamines |
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Authors: | Kubota Katsumi Kurebayashi Hirotaka Miyachi Hirotaka Tobe Masanori Onishi Masako Isobe Yoshiaki |
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Institution: | Dainippon Sumitomo Pharma. Co., Ltd, 3-1-98 Kasagade-naka Konohana-ku Osaka-city, Osaka 554-0022, Japan. |
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Abstract: | A series of tricyclic carboxylic acids having 6-amino-pyrimidine-2,4(1H,3H)-dione with piperazino or homopiperazino moiety linked by propylene, 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, bioavailability in rats, and their anti-inflammatory activity in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, dibenzoxazepine carboxylic acid 13b showed both histamine H(1) receptor antagonistic activity and anti-inflammatory activity in vivo. In addition, 13b exhibited low affinity toward α(1) receptor and low occupancy of H(1) receptor in the brain. It is therefore, believed that 13b is a potential candidate for development as 3rd generation anti-histamine. |
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