Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof

摘要

Macrocyclic compounds that specifically inhibit insulin degrading enzyme (IDE) are provided. Pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, polymorphs, tautomers, isotopically enriched forms, and prodrugs of the macrocyclic IDE inhibitors are also described. Pharmaceutical compositions are also provided. In vivo and in vitro methods of using the IDE inhibitor, and pharmaceutical compositions comprising the IDE inhibitor, for example, for the inhibition of IDE in a subject exhibiting aberrant IDE activity, impaired insulin signaling, or insulin resistance, for example, a subject having diabetes, are also provided.

主权项

1. A method of treating a disease, disorder, or condition associated with aberrant insulin degrading enzyme (IDE) activity, impaired insulin signaling, or insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, wherein:
is a single or double C—C bond, wherein when is a double C—C bond, then indicates that the adjacent C═C double bond is in a cis or trans configuration;R1 is hydrogen; substituted or unsubstituted aliphatic; or substituted or unsubstituted heteroaliphatic;R2 is hydrogen; halogen; substituted or unsubstituted aliphatic; or substituted or unsubstituted heteroaliphatic;R5 is substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted amino; —C(═O)—N(RJ)2; —C(═O)—ORJ; —C(═O)—SRJ; or —CH2—C(═O)N(RJ)2; wherein each occurrence of RJ is independently hydrogen; a protecting group; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RJ groups are joined to form a substituted or unsubstituted heterocyclic group; optionally wherein R5 further comprises a label, resin, or therapeutic agent attached thereto;each instance of RE, RF, RG, RH, and RI is independently hydrogen; substituted or unsubstituted acyl; a nitrogen protecting group; substituted or unsubstituted aliphatic; or substituted or unsubstituted heteroaliphatic;n is 0 or an integer between 1 and 10, inclusive; andm is an integer between 1 and 5, inclusive.