Synthesis and structure–activity relationship of tricyclic carboxylic acids as novel anti-histamines

• Published in: Bioorganic & medicinal chemistry 2011-05, Vol.19 (9), p.3005-3021
• Main Authors: Kubota, Katsumi, Kurebayashi, Hirotaka, Miyachi, Hirotaka, Tobe, Masanori, Onishi, Masako, Isobe, Yoshiaki
• Format: Article
• Language: English
• Subjects: Animals; Anti-histamine; Anti-inflammatory; anti-inflammatory activity; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; bioavailability; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; brain; Caco-2 Cells; carboxylic acids; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cell Membrane Permeability; Cyclization; Dibenzoxazepine; H 1 receptor antagonist; histamine; Histamine and antagonists. Allergy; Histamine H1 Antagonists - chemical synthesis; Histamine H1 Antagonists - chemistry; Histamine H1 Antagonists - pharmacology; human cell lines; Humans; Medical sciences; Mice; Oxazepines - chemical synthesis; Oxazepines - chemistry; Oxazepines - pharmacology; permeability; Pharmacology. Drug treatments; propylene; Protein Binding; Pyrimidine-2,4(1 H,3 H)-dione; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Receptors, Histamine H1 - chemistry; Receptors, Histamine H1 - metabolism; Structure-Activity Relationship; structure-activity relationships
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.03.003

A series of tricyclic carboxylic acids having 6-amino-pyrimidine-2,4(1 H,3 H)-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.