Substrate selective inhibitors of insulin-degrading enzyme (IDE) and uses thereof
Provided herein are compounds of Formulae (RL), (I), (II), (III), (IV), and (V), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, prodrugs, and isotopically labeled derivatives thereof. Also provided are pharmaceutical compositions, kits, and methods involving the inventive compounds for the treatment of metabolic disorders (e.g., diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, obesity). The compound are useful as substrate selective inhibitors of insulin-degrading enzyme (IDE).
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof,
wherein:
G 1 is of formula:
Ring A is carbocyclylene, heterocyclylene, arylene, or heteroarylene;
R 1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —CH 2 -halo, —CH 2 OR 1a , —CH 2 SR 1a , or —CH 2 N(R 1a ) 2 , wherein each R 1a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 1a are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring;
R 2 is of formula:
wherein:
L 1 is a bond, and Ring B is a heterocyclic ring,
each R 9 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 9a , —N(R 9a ) 2 , —S(═O) 2 R 9a , —S(═O) 2 OR 9a , or —S(═O) 2 N(R 9a ) 2 , wherein each R 9a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 9a are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; and
k is 0, 1, 2, 3, 4, or 5;
each R 3 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 3a , or —N(R 3a ) 2 , wherein each R 3a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 3a are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring;
each R 4 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —OR 4a , or —N(R 4a ) 2 , wherein each R 4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 4a are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring;
R 5 is of formula:
m is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, 3, or 4.
2. The compound of claim 1 , wherein R 2 is of formula:
wherein:
L 1 is a bond;
Ring B is
and
each R 9 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 9a , —N(R 9a ) 2 , —S(═O) 2 R 9a , —S(═O) 2 OR 9a , or —S(═O) 2 N(R 9a ) 2 , wherein each R 9a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 9a are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring.
3. The compound of claim 1 , wherein R 1 is optionally substituted alkyl.
4. The compound of claim 1 , wherein k is 0 or 1.
5. The compound of claim 4 , wherein R 9 is halogen, optionally substituted C 1-6 alkyl, or —OR 9a .
6. The compound of claim 1 , wherein m is 0 or 1.
7. The compound of claim 1 , wherein p is 0 or 1.
8. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.
10. A method of treating a metabolic disorder associated with insulin-degrading enzyme comprising administering a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, to a subject with the metabolic disorder.
11. The compound of claim 1 , wherein the compound is of Formula (I):
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein R 1 is CH 2 OR 1a .
13. The compound of claim 1 , wherein R 5 is of formula:
14. The compound of claim 1 , wherein R 5 is
15. A compound of formula:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
16. A compound of formula:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
17. The compound of claim 1 , wherein Ring A is arylene.
18. The compound of claim 1 , wherein Ring A is phenylene.
19. The compound of claim 1 , wherein R 2 is of formula:
L 1 is a bond, and Ring B is