Spiruchostatin derivatives and their therapeutic use

摘要

Spiruchostatin derivatives and their therapeutic use Depsipeptide spiruchostatin analogues of the general formula (IX) or (X), isosteres or pharmaceutically acceptable salts thereof, useful in the inhibition of histone deacetylase (HDAC), wherein X is -C(=O)N(R10)- or -CH(OPr3)-; R7, R9and R10are each independently hydrogen or a natural or unnatural amino acid side chain moiety; Pr1and Pr2are independently hydrogen or a thiol protecting group; Pr3is hydrogen or an alcohol protecting group and R1, R2, R5and R6are each independently hydrogen, a natural or unnatural amino acid side chain moiety, or R1and R2and/or R5and R6taken together with the carbon atom to which they are attached form a spirocyclic fragment, with the proviso that R1and R2are not both hydrogen or R5and R6are not both hydrogen. The use of such compounds in treatment of cancer, cardiac hypertrophy, chronic heart failure, an inflammatory condition, a cardiovascular disease, a haemoglobinpathy, a thalassemia, a sickle cell disease, a CNS disorder, an autoiminune disease, diabetes, osteoporosis, MDS, benign prostatic hyperplasia, endometriosis, oral leukoplakia, a genetically related metabolic disorder, an infection, Rubens-Taybi, fragile X syndrome or alpha-1 antitrypsin deficiency is outlined. Methods for assaying HDAC inhibition and pharmaceutical compositions comprising such compounds are also provided.