Enkephalin conjugates
View Patent ↗The present invention relates to amphiphilic drug-oligomer conjugates capable of traversing the blood-brain barrier (“BBB”) and to methods of making and using such conjugates. An amphiphilic drug-oligomer conjugates comprise a therapeutic compound conjugated to an oligomer, wherein the oligomer comprises a lipophilic moiety coupled to a hydrophilic moiety. The conjugates of the invention further comprise therapeutic agents such as proteins, peptides, nucleosides, nucleotides, antiviral agents, antineoplastic agents, antibiotics, etc., and prodrugs, precursors, derivatives and intermediates thereof, chemically coupled to amphiphilic oligomers.
1. An amphiphilic drug-oligomer conjugate comprising a therapeutic compound consisting of an enkephalin compound selected from the group consisting of SEQ ID NOS: 1 or 48 conjugated to an oligomer, wherein the oligomer comprises a lipophilic moiety coupled to a hydrophilic moiety, and wherein the oligomer has the formula:
CH 3 (CH 2 ) x (CH 2 CH═CH) y (CH 2 ) z A(OC 2 H 4 ) m (OC 2 H 4 ) n E
wherein
m=1 to 6;
n=0 or 1;
x=0, 3 or 6;
y=1, 2, 3 or 6;
z=2, 3, 7 or 8;
A=single bond, CO or CONHCH 2 CH 2 ; and
E=OH or OCH 2 COOH.
2. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the amphiphilic drug-oligomer conjugate exhibits the biological activity of the therapeutic compound without cleavage of the therapeutic compound from the oligomer.
3. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the amphipilic drug-oligomer conjugate does not exhibit the biological activity of the therapeutic compound without cleavage of the therapeutic compound from the oligomer.
4. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the lipophilic moiety is coupled to the hydrophilic moiety by a hydrolyzable bond.
5. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the lipophilic moiety is coupled to the hydrophilic moiety by a non-hydrolyzable bond.
6. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the lipophilic moiety is coupled to the hydrophilic moiety by a bond selected from the group consisting of: amide bond, carbamate bond, carbonate bond and ester bond.
7. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the oligomer is coupled to the therapeutic compound by a bond selected from the group consisting of amide bond, carbamate bond, carbonate bond and ester bond.
8. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the enkephalin compound comprises an added N-terminal residue selected from the group consisting of proline and alanine.
9. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the enkephalin compound is met-enkephalin-lys (SEQ ID NO:1) or an analog thereof.
10. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the enkephalin compound is met 5 -enkephalin (SEQ ID NO:48) or an analog thereof.
11. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the therapeutic compound is met-enkephalin-lys (SEQ ID NO:1) and the oligomer has the formula:
CH 3 (CH 2 ) x (CH 2 CH═CH) y (CH 2 ) z A(OC 2 H 4 ) m (OC 2 H 4 ) n E
wherein m=1, n=0, A=CONHCH 2 CH 2 , E=OH, x=0, y=6, and z=2.
12. The amphiphilic drug-oligomer conjugate of claim 1 , wherein the therapeutic compound is met-enkephalin-lys (SEQ ID NO: 1) and the oligomer has the formula:
CH 3 (CH 2 ) x (CH 2 CH═CH) y (CH 2 ) z A(OC 2 H 4 ) m (OC 2 H 4 ) n E
wherein m=1, n=0, A=CONHCH 2 CH 2 , E=OH, x=3, y=2, and z=7.