Synthesis and assessment of ethylene diamine-based self-immolative linkers for use in the selective delivery of drugs to bones

Self-immolative linkers containing bisphosphonates may be an ideal approach to delivering drugs to bone for treatment of diseases such as osteoporosis. Bisphosphonates can be used to target pro-drugs to bone and can be linked to active drugs via a self-immolative linker such as an ethylene diamine carbamate. Such prodrugs can be inactive until reaching and attaching to bone where they then slowly release the active drug. Several prodrug models with an ethylene diamine linker attached to a model drug, 1-phenyl-2,2,2-trifluoroethanol (which represents a structural component of a proprietary bone stimulating drug) were prepared and used to study the effect of the position of attachment of the model drug and the bisphosphonate and of substitutions on the linker on the rate of self-immolation and drug release. This study concluded that attachment of the bisphosphonate, steric hindrance, and steric compression (attributable to substitutions) can be used to alter the rate of self-immolation.