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

Katsumi Kubota; Hirotaka Kurebayashi; Hirotaka Miyachi; Masanori Tobe; Masako Onishi; Yoshiaki Isobe

doi:10.1016/j.bmc.2011.03.003

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

Bioorg Med Chem. 2011 May 1;19(9):3005-21. doi: 10.1016/j.bmc.2011.03.003. Epub 2011 Mar 11.

Authors

Katsumi Kubota¹, Hirotaka Kurebayashi, Hirotaka Miyachi, Masanori Tobe, Masako Onishi, Yoshiaki Isobe

Affiliation

¹ Dainippon Sumitomo Pharma. Co., Ltd, 3-1-98 Kasagade-naka Konohana-ku Osaka-city, Osaka 554-0022, Japan.

PMID: 21470866
DOI: 10.1016/j.bmc.2011.03.003

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.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacology
Azepines / chemical synthesis
Azepines / chemistry
Azepines / pharmacology
Caco-2 Cells
Carboxylic Acids / chemical synthesis
Carboxylic Acids / chemistry*
Carboxylic Acids / pharmacology
Cell Membrane Permeability
Cyclization
Histamine H1 Antagonists / chemical synthesis
Histamine H1 Antagonists / chemistry*
Histamine H1 Antagonists / pharmacology
Humans
Mice
Oxazepines / chemical synthesis
Oxazepines / chemistry
Oxazepines / pharmacology
Protein Binding
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology
Rats
Receptors, Histamine H1 / chemistry
Receptors, Histamine H1 / metabolism
Structure-Activity Relationship

Substances

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
Anti-Inflammatory Agents
Azepines
Carboxylic Acids
Histamine H1 Antagonists
Oxazepines
Pyrimidines
Receptors, Histamine H1