Inhibitors of leukotriene B4. Synthesis and sar of new ß-enaminoester open-chain analogues of zeneca ZD2138

A series of methoxy tetrahydropyranyl ß-enaminoesters has been discovered as inhibitors of LTB4 production. These are unusual open chain analogues of Zeneca ZD2138, the highly potent orally active 5-LO inhibitor under development for the treatment of asthma and rheumatoid arthritis. In vitro, compound 1a inhibited LTB4 formation in human whole blood with an IC50 of 0.04 μM. In inflamed exudate in the rat 1a inhibited formation of LTB4 with an oral ED50 3h after dosing of 3.0 mg/kg.