RESUMO
A series of N-hydroxycarbamates containing a histaminergic H(1) receptor antagonist pharmacophore was synthesized. In vitro assays determined the compounds had both histaminergic binding and 5-lipoxygenase inhibiting activities comparable to the corresponding N-hydroxyurea analog. Animal models demonstrated antihistaminergic and the 5-lipopxygenase inhibitory activity, with the N-hydroxyurea analog having a better overall profile.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Lipoxigenase , Animais , Sangue , Cobaias , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/química , Humanos , Ácidos Hidroxâmicos/farmacologia , Concentração Inibidora 50 , Leucotrieno B4/biossíntese , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of compounds possessing both H(1) histamine receptor antagonist and 5-lipoxygenase (5-LO) inhibitory activities was synthesized. The H(1)-binding scaffolds of cetirizine, efletirizine, and loratadine were linked to a lipophilic N-hydroxyurea, the 5-LO inhibiting moiety of zileuton. Both activities were observed in vivo, as was increased CYP3A4 inhibition compared to their respective single-function drugs. Selected analogs in the series were shown to be orally active in guinea pig models.
Assuntos
Cetirizina/química , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Inibidores de Lipoxigenase , Loratadina/química , Animais , Cetirizina/farmacocinética , Cobaias , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/química , Loratadina/farmacocinética , Modelos Animais , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A series of novel compounds with both 5-lipoxygenase (5-LO) inhibitory and histamine H(1) receptor antagonist activity were designed for the treatment of asthma. These dual-function compounds were made by connecting 5-LO and H(1) pharmacophores,N-hydroxyureas and benzhydryl piperazines, respectively. A range of in vitro activities was observed, with the furan analog 10 demonstrating both activities in an animal model. The activities observed were compared to single-function drugs.
