Regulation of substrate activity

• US 20060052310A1
• Filed: 07/27/2005
• Published: 03/09/2006
• Est. Priority Date: 08/21/1998
• Status: Active Grant

• Current Assignee: DARA Biosciences Incorporated (Barings LLC (Private Equity))
• Original Assignee: Point Therapeutics, Inc. (Barings LLC (Private Equity))
• Inventors: Wallner, Barbara P.
• Granted Patent: US 7,265,118 B2
• Time in Patent Office: Days
• US Class Current: 514/20.100
• CPC Class Codes: A61K 31/69 Boron compounds

Abstract

A method for regulating substrate activity in vivo is useful for the treatment of medical disorders such as inflammation, arteriolosclerosis and angiogenesis. The method involves the administration of an effective amount of a DPP-IV inhibitor to a patient in need of such treatment.

Claims

1. A method for treating a medical disorder in a subject mediated by the alteration of substrate activity comprising administering to the subject an effective amount of a compound having the formula PR, wherein P represents a targeting moiety that binds to DPP-IV, and R represents a reactive group that reacts a reactive center of DPP-IV, said amount being sufficient to prevent chemokine alteration by inhibiting DPP-IV activity.

2. The method of claim 1 wherein the compound has the formula

3. The method of claim 1 wherein the compound has the formula

4. The method of claim 1 wherein the compound has the formula

5. The method of claim 1 wherein the compound is a five membered unsaturated ring having two nitrogen atoms.

6. The method of claim 5 wherein the compound is an imidazole ring.

7. The method of claim 1 wherein the compound has the formula

8. The method of claim 7 wherein T is a boronate group, a phosphonate group, a cyano group, or a trifluoroalkyl ketone group;

each R₁ and R₂ is H, each Y is CH₂—

CH₂;

each R is independently chosen from the R group of proline and alanine;

the inhibitory compound has a binding or dissociation constant to DPP-IV of at least 10<sup>−

9</sup>M; and

each D1 and D2 is, independently, F, or D1 and D2 together are a ring containing 1 to 20 carbon atoms, and optionally heteroatoms which can be N, S, or O.

9. The method of claim 7 wherein the compound has the formula

10. The method of claim 9 wherein the compound is Val-boroPro.

11. The method of claim 9 wherein the compound is cyclic Xaa-boroPro.

12. The method of claim 1 wherein the substrate is selected from the group consisting of SDF-1, RANTES, MIP-1, MIP-3, GLP-2, G-CSF, EPO, IL-6, IL-11, IL-8, Substance P, fibronectin, and monomeric fibrin.

13. The method of claim 1 wherein the medical condition is selected from the group consisting of arteriolosclerosis, allergies, inflammation, angiogenesis, cardiogenesis, neoplasm, tumor, cancer, a hepatic disease, an intestinal disease, organ vascularization, and microbial and viral infections.

14. The method of claim 1 wherein the compound is given to the subject by oral administration.

15. The method of claim 1 wherein the compound is given to the subject by parenteral administration.

16. The method of claim 1 wherein the effective amount is in the range of 0.01 mg/kg per day to 100 mg/kg per day.

17. A pharmaceutical composition for treating a medical disorder in a subject mediated by chemokine inactivation comprising

a pharmaceutically acceptable carrier;

and

an effective amount of a compound having the formula

where T is selected from a group of the formula;

where each D₁ and D₂, independently, is a hydroxyl group or a group which is capable of being hydrolyzed to a hydroxyl group in aqueous solution at physiological pH;

a group of the formula;

where G is either H, F, or an alkyl group containing 1 to 20 carbon atoms and, optionally, heteroatoms which can be N, S or O;

a phosphonate group of the formula;

where each J, independently, is any number of C, H, O, S or N atoms in any combination, or O-alkyl, N-alkyl, or alkyl, each O-alkyl, N-alkyl or alkyl containing 1-20 carbon atoms and, optionally, heteroatoms which can be N, S, or O;

a group of formula

a group of formula

where R is an alkyl, or aryl group and may be substituted or unsubstituted, an alphaketo ester;

or a group of formula

Y is a group of formula;

and each R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are H;

B is boron;

X is any number of C, H, O, S, or N atoms; and

m can vary from 0 to 20.

18. The composition of claim 17 wherein T is a boronate group, a phosphonate group, a cyano group, or a trifluoroalkyl ketone group;

each R₁ and R₂ is H, each Y is CH₂—

CH₂;

each R is independently chosen from the R group of proline and alanine;

the inhibitory compound has a binding or dissociation constant to DPP-IV of at least 10<sup>−

9</sup>M; and

each D1 and D2 is, independently, F, or D1 and D2 together are a ring containing 1 to 20 carbon atoms, and optionally heteroatoms which can be N, S, or O.

19. A pharmaceutical composition for treating a medical disorder in a subject mediated by chemokine inactivation comprising

a pharmaceutically acceptable carrier;

and

an effective amount of a compound having the formula

where each D₁ and D₂ is a hydroxyl group;

wherein X an amino acid; and

wherein C is bonded to B in the L-configuration.

20. The method of claim 19 wherein the compound is Val-boroPro.

21. The method of claim 19 wherein the compound is cyclic Xaa-boroPro.