Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
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.
1. 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;
R 1 is —CH 2 CH 2 CH 2 CH 2 —NH 2 ;
R 2 is hydrogen; halogen; substituted or unsubstituted aliphatic; or substituted or unsubstituted heteroaliphatic;
R 5 is substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted amino; —C(═O)—N(R J ) 2 ; —C(═O)—OR J ; —C(═O)—SR J ; or —CH 2 —C(═O)N(R J ) 2 , wherein each occurrence of R J 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 R J groups are joined to form a substituted or unsubstituted heterocyclic group;
each instance of R E , R F , R G , R H , and R I is independently hydrogen; a nitrogen protecting group; substituted or unsubstituted aliphatic; or substituted or unsubstituted heteroaliphatic;
n is 0 or an integer between 1 and 10, inclusive; and
m is an integer between 1 and 5, inclusive.
2. The compound of claim 1 , wherein the compound is of Formula (VI):
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof.
3. The compound of claim 1 , wherein n is 1.
4. The compound of claim 1 , wherein m is 4.
5. The compound of claim 1 , wherein the compound is of Formula (H):
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof.
6. The compound of claim 1 , wherein R 2 is hydrogen or —(CH 2 ) q —CH 3 , wherein q is 0 or an integer between 1 and 10, inclusive.
7. The compound of claim 1 , wherein R 5 is —C(═O)NH 2 , or —CH 2 —C(═O)NH 2 .
8. The compound of claim 1 , wherein represents a double bond.
9. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof.
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, in an amount effective to inhibit IDE in a subject, and optionally a pharmaceutically acceptable carrier.
11. An in vitro method of inhibiting the activity of an insulin degrading enzyme (IDE) comprising contacting an IDE with the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, in an amount effective to inhibit the activity of IDE.
12. An in vivo method of inhibiting the activity of an insulin degrading enzyme (IDE) comprising contacting an IDE with the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, in an amount effective to inhibit the activity of IDE.
13. The method of claim 12 , wherein the IDE molecule is contacted with the compound, the pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, or the composition in a subject.
14. The method of claim 13 , wherein the subject exhibits impaired insulin signaling or insulin resistance.
15. The method of claim 14 , wherein the subject has diabetes.
16. A method of treating a disease, disorder, or condition associated with impaired insulin signaling or insulin resistance, the method comprising administering a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, to a subject in need thereof.
17. The compound of claim 8 , wherein each of R E , R F , R G , and R I is hydrogen.
18. The compound of claim 17 , wherein n is 1 and m is 4.
19. The compound of claim 18 , wherein R 2 is hydrogen.
20. The compound of claim 19 , wherein R 5 is —C(═O)—N(R J ) 2 .
21. The compound of claim 1 , wherein R 5 is —C(═O)—N(R J ) 2 .
22. The compound of claim 1 , wherein the compound is of Formula (VIII):
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof.
23. The method of claim 16 , wherein the disease, disorder, or condition is diabetes.
24. The method of claim 16 , wherein the disease, disorder, or condition is metabolic syndrome.