RESUMO
We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Receptor 7 Toll-Like/agonistas , Água/química , Adenina/administração & dosagem , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , SolubilidadeRESUMO
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.
Assuntos
Anti-Inflamatórios/química , Ácidos Carboxílicos/química , Antagonistas dos Receptores Histamínicos H1/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Azepinas/síntese química , Azepinas/química , Azepinas/farmacologia , Células CACO-2 , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Permeabilidade da Membrana Celular , Ciclização , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Camundongos , Oxazepinas/síntese química , Oxazepinas/química , Oxazepinas/farmacologia , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Receptores Histamínicos H1/química , Receptores Histamínicos H1/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of phenothiazine carboxylic acid derivatives, having 6-amino-pyrimidine-2,4(1H,3H)-dione moiety via a appropriate linker, 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 and bioavailability in rats. Finally, promising compounds were examined for their anti-inflammatory potential in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, phenothiazineacetic acid compound 27 showed both histamine H(1)-receptor antagonistic activity and anti-inflammatory activity in vivo model.
