A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules

摘要: Asthma, like many inflammation related disorders, has a complex etiology. Drugs targeting multiple pathways may prove more efficacious in these disorders. Cyclic 3′,5′-adenosine monophosphate (cAMP) phosphodiesterase IV (PDE IV) is one of the validated targets bronchial asthma and despite availability some therapeutic molecules PDE IV, with better properties are desired. Eosinophil/neutrophil infiltration into lung also be an important component which increased expression epithelial cell adhesion play role. This study describes synthesis novel class compounds ‘triazine-aryl-bis-indoles’ having catechol derived structure constituting part ‘triazine’ ‘bis-indole’ moiety on it. potently inhibited both ICAM-1 VCAM-1. The best molecule this (compound 11) activity vitro, IC50 value 14 μM compared to 12.7 for existing drug rolipram. compound 11 not only stabilized cAMP level human cells (L132) following stimulation forskolin, but TNF-α induced such as VCAM-1 umbilical vein (HUVECs). It significantly neutrophils endothelial monolayer (IC50 = 17.86 μM) dose dependent manner. Its absolute bioavailability (in mice) was found 70% its toxicity pharmacokinetic profiles excellent. dual suggests that could have broad applications neutrophil dominant diseases severe asthma, COPD acute injury.