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

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Kubota K, Kurebayashi H, Miyachi H, Tobe M, Onishi M, Isobe Y

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.

PubMed ID

21470866 [ View in PubMed

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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 alpha(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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Fexofenadine	Histamine H1 receptor	IC 50 (nM)	78	N/A	N/A	Details
Ketotifen	Histamine H1 receptor	IC 50 (nM)	1	N/A	N/A	Details