Polysubunit opioid prodrugs resistant to overdose and abuse
The invention provides compositions and methods for the treatment or prevention of pain. The invention provides constructs whereby hydrolysis of the construct by a specified gastrointestinal enzyme directly, or indirectly, releases an opioid when taken orally as prescribed. The gastrointestinal enzyme mediated release of opioid from constructs of the invention is designed to be attenuated in vivo via a saturation or inhibition mechanism when overdoses are ingested. The invention further provides constructs that are highly resistant to oral overdose, chemical tampering, and abuse via non-oral routes of administration.
1. A compound represented by the structure of Formula (I):
or a salt thereof, wherein:
Q is independently selected from optionally substituted heteroalkyl and optionally substituted alkyl;
L 1 is independently at each occurrence absent or a cleavable or non-cleavable linker;
L 2 is independently at each occurrence absent or a cleavable or non-cleavable linker;
R 1 is independently selected at each occurrence from a GI enzyme substrate, a GI enzyme inhibitor, and an opioid antagonist;
R 2 is an opioid agonist covalently bound to a GI enzyme substrate; and
m and n are independently selected at each occurrence from 1 to 1,000,000.
2. The compound or salt of claim 1 , wherein Q is an optionally substituted heteroalkyl group.
3. The compound or salt of claim 2 , wherein Q is an optionally substituted peptide.
4. The compound or salt of claim 3 , wherein Q is an optionally substituted peptide with from 1 to 500 amino acids.
5. The compound or salt of claim 4 , wherein Q is an optionally substituted peptide with from 1 to 50 amino acids.
6. The compound or salt of claim 5 , wherein Q is an optionally substituted peptide with from 1 to 10 amino acids.
7. The compound or salt of claim 6 , wherein Q is an optionally substituted peptide with from 1 to 3 amino acids.
8. The compound of claim 1 , wherein the compound of Formula (I) is represented by a structure of Formula (IA), (IB), or (IC):
wherein W is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, and optionally substituted alkoxycarbonyl.
9. The compound of claim 1 , wherein the compound of Formula (I) is represented by a structure of Formula (ID), (IE), or (IF):
10. The compound of claim 1 , wherein R 1 is independently selected at each occurrence from a GI enzyme inhibitor.
11. The compound or salt of claim 10 , wherein R 1 at each occurrence is a serine protease inhibitor.
12. The compound or salt of claim 10 , wherein R 1 at each occurrence is a trypsin inhibitor.
13. The compound of claim 1 , wherein R 1 -L 1 is independently selected at each occurrence from:
wherein:
Y is independently selected from an amidine, guanidine, benzylamine, alkyl substituted amidine, alkyl substituted guanidine, alkyl substituted benzylamine, benzylguanidine, alkyl substituted benzylamidine, or alkyl substituted benzyl; and
Z is independently selected from hydrogen, cyano, nitro, halogen, alkyl and alkoxy.
14. The compound or salt of claim 13 , wherein Y is amidine.
15. The compound or salt of claim 13 , wherein R 1 -L 1 is represented by the formula:
16. The compound of claim 1 , wherein L 1 at each occurrence is selected from a cleavable or non-cleavable linker including from 2 to 15 atoms.
17. The compound or salt of claim 15 , wherein L 1 is —O—CH 2 —CH 2 —NH— or —O—CH 2 —CH 2 —O—.
18. The compound of claim 1 , wherein n is selected from 1 to 20.
19. The compound or salt of claim 18 , wherein n is selected from 1 to 10.
20. The compound or salt of claim 19 , wherein n is selected from 1 to 3.
21. The compound of claim 1 , wherein R 2 -L 2 is independently selected at each occurrence from:
wherein:
D is an opioid agonist;
R 101 and R 102 are independently selected from optionally substituted alkyl, an amino acid side chain and an amino acid side-chain mimic.
22. The compound or salt of claim 21 , wherein R 101 is selected from an amino acid side chain and R 102 is optionally substituted alkyl.
23. The compound or salt of claim 21 , wherein R 101 is selected from an arginine or lysine side chain and R 102 is optionally substituted methyl.
24. The compound or salt of claim 23 , wherein R 102 is methyl substituted with —NH-acetyl.
25. The compound of claim 1 , wherein D is selected from morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, and buprenorphine.
26. The compound of claim 1 , wherein D is represented by the formula:
27. The compound of claim 1 , wherein m is selected from 1 to 20.
28. The compound or salt of claim 27 , wherein m is selected from 1 to 10.
29. The compound or salt of claim 28 , wherein m is 1 to 3.
30. The compound of claim 1 , wherein said compound is represented by the formula:
or a salt thereof.
31. The compound of claim 1 , wherein the compound is represented by the formula:
or a salt thereof.
32. The compound of claim 1 , wherein the compound is represented by the formula:
or a salt thereof.
33. The compound of claim 1 , wherein the compound is represented by the formula:
or a salt thereof.
34. A pharmaceutical formulation comprising a composition of claim 1 and a pharmaceutically acceptable excipient.
35. A method of treating pain in a subject in need thereof, the method comprising administrating to the subject a therapeutically-effective amount of a composition of claim 1 .