title: Synthesis and structure-activity relationship of tricyclic carboxylic acids as novel anti-histamines.
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.
authors.affiliation: Dainippon Sumitomo Pharma. Co., Ltd, 3-1-98 Kasagade-naka Konohana-ku Osaka-city, Osaka 554-0022, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Kubota
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kurebayashi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Miyachi
authors.forename: Masanori
authors.initials: M
authors.lastname: Tobe
authors.forename: Masako
authors.initials: M
authors.lastname: Onishi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002463:Cell Membrane Permeability; D003500:Cyclization; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C560338:5-(3-(4-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-1,4-diazepan-1-yl)propyl)-5,11-dihydrodibenzo(b,e)(1,4)oxazepine-7-carboxylic acid; D000893:Anti-Inflammatory Agents; D001381:Azepines; D002264:Carboxylic Acids; D006634:Histamine H1 Antagonists; D010077:Oxazepines; D011743:Pyrimidines; D011969:Receptors, Histamine H1