Methods of activating receptor using amphiphilic drug-oligomer conjugates

• US 20040110735A1
• Filed: 11/19/2003
• Published: 06/10/2004
• Est. Priority Date: 08/14/1998
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Aslam M. Ansari, Balasingam Radhakrishnan, Christopher H. Price, Nnochiri N. Ekwuribe, Wesley R. Anderson Jr
• Inventors: Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Price, Christopher H., Ansari, Aslam M., Anderson, Wesley R. Jr.
• Granted Patent: US 6,930,090 B2
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 of the parathyroid hormones

Abstract

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 conjugate comprises 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.

Claims

1. A method of activating a receptor, comprising bringing said receptor into contact with an amphiphilic drug-oligomer conjugate comprising a therapeutic compound conjugated to an oligomer, wherein the oligomer comprises a lipophilic moiety coupled with a hydrophilic moiety.

2. The method of claim 1, further characterized in that said conjugate exhibits activity without cleavage of the therapeutic compound from the oligomer.

3. The method of claim 1, wherein the receptor is a G-protein coupled receptor.

4. The method of claim 1, wherein the receptor is an opioid receptor.

5. The method of claim 1, wherein the receptor is an opioid receptor selected from the group consisting of δ

, μ

, and κ

.

6. The method of claim 1, wherein the hydrophilic moiety is selected from the group consisting of sugar and PEG_1-7.

7. The method of claim 1, wherein the hydrophilic moiety is selected from the group consisting of fatty acid, alkyl 1-26, cholesterol and adamantane.

8. The method of claim 1, wherein the therapeutic compound is a peptide having an added N-terminal residue selected from the group consisting of proline and alanine.

9. The method of claim 1, wherein the therapeutic compound is a peptide or protein.

10. The method of claim 1, wherein the therapeutic compound is a peptide and the peptide is selected from the group consisting of:

enkephalin, adrenocorticotropic hormone, adenosine deaminase, ribonuclease, alkaline phosphatase, angiotensin, antibodies, arginase, arginine deaminease, asparaginase, caerulein, calcitonin, chemotrypsin, cholecystokinin, clotting factors, dynorphins, endorphins, enkephalins, erythropoietin, gastrin-releasing peptide, glucagon, hemoglobin, hypothalmic releasing factors, interferon, katacalcin, motilin, neuropeptide Y, neurotensin, non-naturally occurring opioids, oxytocin, papain, parathyroid hormone, -prolactin, soluble CD-4, somatomedin, somatostatin, somatotropin. superoxide dismutase, thyroid stimulating hormone, tissue plasminogen activator, trypsin, vasopressin, and analogues and active fragments of such peptides.

11. The method of claim 1, wherein the amphiphilic oligomer is selected from the group consisting of:

CH₃(CH₂)_n(OC₂H₄)_mOH 

 

(Formula

     1);

wherein n=3 to 25 and m=1 to 6;

CH₃(CH₂)_n(OC₂H₄)_mOCH₂CO₂H 

 

(Formula

     2);

wherein n=3 to 25 and m=1 to 7;

CH₃(CH₂)_nCX(OC₂H₄)_mOH 

 

(Formula

     3);

wherein n=3 to 25, m=1 to 7 and X═

O or N;

R—

(OC₂H₄)_mCH₂CO₂H 

 

(Formula

     4);

wherein m=0 to 5 and R=cholesterol or adamantane;

R—

OCO(C₂H₄₀)_mCH₂CO₂H 

 

(Formula

     5);

wherein m=0 to 5;

CH₃(CH₂—

CH═

CH)₆(CH₂)₂CH₂(OC₂H₄)_mOH 

 

(Formula

     6);

wherein m=0 to 7; and

CH₃(CH H═

CH)₆(CH₂)₂C_x(OC₂H₄)_mOH 

 

(Formula

     7);

wherein m=1 to 7 and X═

N or 0.

12. The method of claim 1, wherein the hydrophilic moiety is coupled to the hydrophobic moiety by a hydrolyzable bond.

13. The method of claim 1, wherein the hydrophilic moiety is coupled to the hydrophobic moiety by a non-hydrolyzable bond.

14. The method of claim 1, wherein the therapeutic compound is an opioid receptor agonist, antagonist or partial agonist/partial antagonist.

15. The method of claim 1, wherein the therapeutic compound is an enkephalin.