US 2016/0282364 A1 · ASSAY FOR INSULIN-DEGRADING ENZYME (IDE) INHIBITORS

Abstract

IDE-binding probes and assays for the identification of IDE-binding and IDE-inhibiting compounds are provided. Pharmaceutical compositions of macrocyclic IDE inhibitors are also provided, including compositions in which such IDE inhibitors are combined with an additional therapeutic agent. Methods of using IDE inhibitors for transiently inhibiting IDE in a subject in need thereof, for example, for the transient inhibition of IDE in a subject exhibiting aberrant IDE activity, impaired isulin signaling, or insulin resistance, for example, a subject having diabetes, are also provided. Methods of using IDE inhibitors for transiently modulating heart rate and/or blood pressure in a subject are also provided.

Claims31

Dependent claims

A method for identifying insulin-degrading enzyme (IDE)-binding compounds, the method comprising

(a) contacting an IDE with
(i) a probe that binds IDE with an IC50 of 10 μM or less, wherein the probe comprises a detectable label;
and
(ii) a candidate compound,
under conditions suitable for the probe and the candidate compound to bind the IDE;
(b) determining the level of unbound probe in the presence of the candidate compound;
and
(c) comparing the level of unbound probe determined in step (b) to a reference level, wherein if the level of unbound probe in the presence of the candidate compound is higher than the reference level, then the candidate compound is identified as an IDE-binding compound.

5 more elements

A compound of Formula (V):

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug 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;
halogen;
substituted or unsubstituted aliphatic;
substituted or unsubstituted heteroaliphatic;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl;
substituted or unsubstituted acyl;
—ORA;
—N(RA)2;
—SRA;
═O;
—CN;
—NO2;
—SCN;
—SORA;
or —SO2RA;
wherein each occurrence of RA 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;
R2 is hydrogen;
halogen;
substituted or unsubstituted aliphatic;
substituted or unsubstituted heteroaliphatic;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl;
substituted or unsubstituted acyl;
—ORB;
—N(RB)2;
—SRB;
═O;
—CN;
—NO2;
—SCN;
—SORB;
or SO2RB;
wherein each occurrence of RB 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;
R5 comprises a detectable label and, optionally, a linker;
each instance of RE, RF, RG, RH, and RI is independently hydrogen;
substituted or unsubstituted acyl;
a nitrogen protecting group;
substituted or unsubstituted aliphatic;
substituted or unsubstituted heteroaliphatic;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl;
substitute or unsubstituted hydroxyl;
substituted or unsubstituted thiol;
substituted or unsubstituted amino;
or halogen;
n is 0 or an integer between 1 and 10, inclusive;
and
m is an integer between 1 and 5, inclusive.

61 more elements

Dependencies are inferred from the claim text.

Assay for insulin-degrading enzyme (ide) inhibitors

Life of this patent

Assay for insulin-degrading enzyme (ide) inhibitors

Life of this patent

Abstract

Claims31