Synthesis and structure activity relationship of tricyclic carboxylic acids as novel anti histamines.
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 a(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.
Bioorganic medicinal chemistry