Cyclosporin-mitochondrial targeting group conjugates useful in the treatment of ischaemia/reperfusion injury and neurodegenerative diseases

摘要

Conjugates, or pharmaceutically acceptable salts, comprising a cyclosporin moiety of formula (I) linked to one or more mitochondrial targeting groups.A is B is methyl or ethyl. One of R1and R1* is hydrogen and the other is methyl. R2is ethyl or isopropyl. R3is hydrogen or methyl. R4is -CH2CH(CH3)CH3, -CH2CH(CH3)CH2CH3, -CH(CH3)CH3or -CH(CH3)CH2CH3. Suitable mitochondrial targeting groups include mitochondrial targeting peptides and liphophilic cations such as a phosphonium, arsonium or ammonium cations, flupritine, MKT-077, pyridinium ceramides, quinoliums, liposomal cations, soribitol. guanidines, cyclic guanidines, rhodamines or a pyridine derivative. In particular, the mitochondrial targeting group may be a triphenylphosphonium cation or rosamine attached via a linker to the cyclosporine moiety at R3or R1. The compounds may be useful as cyclophilin D inhibitors, e.g. in treating ischaemia/reperfusion injury or neurodegenerative disease, or as reagents in assays.