Development of atropisomeric 5N-sulfonyl-1,5-benzodiazepin-2-ones with high inhibitory activity against neutrophil elastase.

Novel 5N-sulfonyl-1,5-benzodiazepin-2-one derivatives (2b, d) with strong inhibition of neutrophil elastase have been developed. The atropisomers of 2d, based on the rotation of the two interlocking sp2-sp2 (Ar-N) axes [(aR, aR) and (aS, aS)], were stably isolated at room temperature by HPLC using a chiral column. A significant difference was observed in the inhibitory activity between the atropisomers [(+)-2d, (-)-2d, and (±)-2d], and the eutomer was revealed to be (+)-2d. The X-ray analysis revealed that the configuration of the eutomer (+)-2d was (aR, aR). The eutomer exhibited approximately 10-fold higher inhibitory activity than the currently used lead compound sivelestat (ONO-0546) (1), indicating its potential as a treatment for acute lung injury. Docking studies with target proteins supported our hypothesis of high activity.