Toward Dual\nTargeting of Catalytic and Gatekeeper\nPockets in Cyclophilins Using a Macrocyclic Scaffold

Cyclophilins, especially cyclophilin A, are involved\nin a variety\nof diseases, including the life cycle of many viruses. An advanced\nmacrocyclic inhibitor of cyclophilin was reported to bind the catalytic\npocket but not the neighboring gatekeeper pocket. Here we describe\nmacrocyclic cyclophilin inhibitors bearing side chains designed to\nreach out to the gatekeeper pocket. After establishing a suitable\nsynthesis allowing for late-stage modification of the relevant positions,\nwe explored this exit vector. This culminated in a rigid ornithine-resembling\nanalogue as a versatile building block, which was also incorporated\ninto the macrocyclic scaffold. The use of amines as the gatekeeper-engaging\nmodality was invalidated, but the exit vector was successfully established\nas a promising position for future modifications. Further work is\nneeded to identify suitable motifs to simultaneously engage the catalytic\nand gatekeeper pockets in this highly developed macrocyclic scaffold.