Modulating a pharmacokinetic property of a drug by administering a bifunctional molecule containing the drug

• US 20050209265A1
• Filed: 12/13/2004
• Published: 09/22/2005
• Est. Priority Date: 11/19/1999
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Crabtree, Gerald R., Wandless, Thomas J., Briesewitz, Roger
• Granted Patent: US 8,044,099 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: Y10S 530/812 Peptides or proteins is immobilized on, or in, an organic carrier

Abstract

Bifunctional molecules and methods for their use are provided. The subject bifunctional molecules are conjugates of a drug moiety and a pharmacokinetic modulating moiety, where these two moieties are optionally joined by a linking group. The bifunctional molecules are further characterized in that they exhibit at least one modulated pharmacokinetic property upon administration to a host as compared to a free drug control. The subject bifunctional molecules find use in a variety of therapeutic applications.

Claims

1. A non-naturally occurring bifunctional molecule of less than about 5000 daltons consisting of a drug moiety and a pharmacokinetic modulating moiety, wherein said drug moiety and said pharmacokinetic modulating moiety are optionally joined by a linking group and said bifunctional molecule exhibits at least one modulated pharmacokinetic property upon administration to a host as compared to a free drug control.

2. The bifunctional molecule according to claim 1, wherein said bifunctional molecule comprises a linking group.

3. The bifunctional molecule according to claim 1, wherein said bifunctional molecule does not include a linking group.

4. The bifunctional molecule according to claim 1, wherein said pharmacokinetic property is selected from the group consisting of half-life, hepatic first-pass metabolism, volume of distribution and degree of blood protein binding.

5. The bifunctional molecule according to claim 1, wherein said pharmacokinetic modulating moiety binds to a protein.

6. The bifunctional molecule according to claim 5, wherein said protein is an extracellular protein.

7. The bifunctional molecule according to claim 5, wherein said protein is an intracellular protein.

8. A synthetic bifunctional molecule of less than about 5000 daltons of the formula:

Z-L-X

wherein;

X is a drug moiety;

L is a bond or a linking group; and

Z is a pharmacokinetic modulating moiety;

wherein X and Z are different and bifunctional molecule exhibits at least one modulated pharmacokinetic property upon administration to a host as compared to a free drug control.

9. The bifunctional molecule according to claim 8, wherein said pharmacokinetic property is selected from the group consisting of half-life, hepatic first-pass metabolism, volume of distribution and degree of blood protein binding.

10. The bifunctional molecule according to claim 8, wherein said drug moiety has a molecular weight of from about 50 to 2000 D.

11. The bifunctional molecule according to claim 8, wherein said drug moiety binds to a protein target.

12. The bifunctional molecule according to claim 8, wherein said pharmacokinetic modulating moiety binds to an extracellular protein.

13. The bifunctional molecule according to claim 8, wherein said pharmacokinetic modulating moiety binds to an intracellular protein.

14. The bifunctional molecule according to claim 8, wherein said bifunctional molecule comprises a linking group.

15. The bifunctional molecule according to claim 8, wherein said pharmacokinetic modulating moiety has substantially no pharmacologic activity apart from binding to an endogenous protein of said host.

16-50. -50. (canceled)