Compounds and Methods for Modulating Vascular Injury

Patent metadata

Field	Value
Publication number	US-2017216238-A1
Application number	US-201615255778-A
Country	US
Kind code	A1
Filing date	Sep 2, 2016
Priority date	Sep 10, 2012
Publication date	Aug 3, 2017
Grant date	—

Abstract

Methods of modulating healing response to vascular injury and/or vascular scarring in a subject are provided. As such, aspects of the disclosure relate to the use of pro-resolving lipid mediators to modulate inflammation and/or restenosis of a vascular wall. Another aspect of the disclosure relates to the use of pro-resolving lipid mediators to modulate a biological activity of vascular smooth muscle cells (VSMC) or vascular endothelial cells (VEC). Pro-resolving lipid mediators that fmd use in the subject methods include derivatives of omega-3 polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids, such as resolvins, protectins, lipoxins and maresins and their therapeutically stable analogs. Also provided are vascular devices and compositions for use in the subject methods. Such methods, devices and compositions fmd use in a variety of applications, including applications related to treatment of vascular injuries and vascular scarring (e.g., restenosis), and applications related to chronic inflammatory diseases of the vascular wall.

First claim

1 . A method of modulating a response to vascular injury or scarring of a vascular wall, the method comprising:
contacting the vascular wall with a pro-resolving lipid mediator in an amount sufficient to modulate the response to the vascular injury or scarring of the vascular wall.

2 . The method of claim 1 , wherein the pro-resolving lipid mediator is a hydroxylated derivative of an omega-3 polyunsaturated fatty acid or an omega-6 polyunsaturated fatty acid.

3 . The method of claim 2 , wherein the omega-3 polyunsaturated fatty acid is eicosapentaenoic acid (EPA) and the pro-resolving lipid mediator is a hydroxylated derivative of EPA.

4 . The method of claim 2 , wherein the omega-6 polyunsaturated fatty acid is docosahexaenoic acid (DHA) and the pro-resolving lipid mediator is a hydroxylated derivative of DHA.

5 . The method of claim 1 , wherein the pro-resolving lipid mediator is selected from the group consisting of resolvins, maresins, protectins, precursors thereof, and derivatives thereof.

6 . The method of claim 1 , wherein the pro-resolving lipid mediator is a D-series resolvin or an E-series resolvin.

7 . The method of claim 1 , wherein the pro-resolving lipid mediator is a Maresin.

8 . (canceled)

9 . The method of claim 1 , wherein the method resolves vascular wall inflammation.

10 . The method of claim 1 , wherein method reduces restenosis of the vascular wall.

11 . The method of claim 6 , wherein the D-series resolvin is a dihydroxylated or a trihydroxylated derivative of docosahexaenoic acid (DHA).

12 . (canceled)

13 . The method of claim 6 , wherein the D-series resolvin is described by formula (I):
HO 2 C—CH 2 —CH 2 -L-CH(OH)—CH 2 —CH═CH—CH 2 —CH 3    (I)
wherein L is a linear C13 hydrocarbon chain comprising:
five —CH═CH— groups; and
three groups independently selected from: —CH 2 —, —(C═O)— and —CH(OH)—.

14 . The method of claim 13 , wherein the D-series resolvin has a 17(S) configuration.

15 . The method of claim 13 , wherein when one or more of the five —CH═CH— groups is present at a position selected from the 4, 7, 10, 13 or 19 positions, the —CH═CH— group at the position has a Z-configuration.

16 . The method of claim 15 , wherein when one or more of the five —CH═CH— groups is present at a position selected from the 5, 6, 8, 9, 11, 12 or 14 positions, the —CH═CH— group at the position has an E-configuration.

17 . The method of claim 13 , wherein L comprises two —CH(OH)— groups and one —CH 2 — group.

18 . The method of claim 13 , wherein L comprises three —CH═CH— groups in the E-configuration and two —CH═CH— groups in the Z-configuration.

19 . The method of claim 18 , wherein L comprises the following group:

20 - 22 . (canceled)

23 . The method of claim 13 , wherein the D-series resolvin is RvD1, RvD2, RvD3 or RvD4.

24 - 66 . (canceled)

67 . A D-series resolvin-containing vascular device for modulating a response to vascular injury or vascular scarring of a vascular wall.

68 . The device of claim 67 , wherein the D-series resolvin is described by formula (I):
HO 2 C—CH 2 —CH 2 -L-CH(OH)—CH 2 —CH═CH—CH 2 —CH 3    (I)
wherein L is a linear C13 hydrocarbon chain comprising:
five —CH═CH— groups; and
three groups independently selected from: —CH 2 —, —(C═O)— and —CH(OH)—.

69 - 70 . (canceled)

Assignees

• Univ California
• Brigham & Womens Hospital Inc

Inventors

• Conte Michael S
• Serhan Charles N
• Desai Tejal A

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/202 Primary

  having three or more double bonds, e.g. linolenic (eicosanoids, e.g. leukotrienes A61K31/557) · CPC title