IP Library › Granted Patent US 12,201,617
Granted Patent B2
US 12,201,617 · App. 18/360,752 · Granted Jan 21, 2025

HDAC6 inhibitors for treatment of metabolic disease and HFpEF

Inventors: Jin Yang (Lexington, MA); Mohammad A. Mandegar (San Francisco, CA); Timothy C. Hoey (Hillsborough, CA)
Assignee: Tenaya Therapeutics, Inc.
A61K31/427A61K31/17A61K31/42A61K31/437A61K31/4439A61K31/505A61K31/5377A61P3/04A61P3/10A61P9/04
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Quick Facts
Patent No.
US 12,201,617
App. No.
18/360,752
Granted
Jan 21, 2025
Kind
B2
Abstract

Provided herein are methods of treating or preventing metabolic disease with an HDAC6 inhibitor. Also provided herein are methods of treating or preventing heart failure with preserved ejection fraction with an HDAC6 inhibitor. A variety of HDAC6 inhibitors are described herein for use in treating or preventing metabolic disease or heart failure with preserved ejection fraction. In one aspect, described herein are methods of treating a human patient by orally administering an HDAC6 inhibitor, such as an inhibitor of Formula (I) or Formula (II).

Claims (48)

1. A method of treating heart failure with preserved ejection fraction (HFpEF) in a subject in need thereof, comprising administering a therapeutically effective amount of an HDAC6 inhibitor to the subject, wherein the HDAC6 inhibitor is a compound according to Formula (Ic):

or a pharmaceutically acceptable salt thereof,

wherein:

R a is H, Me, or F;

R 2 and R 3 are each independently selected from the group consisting of H, alkoxy, aryl, heteroaryl, alkyl, and cycloalkyl, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl;

R 4 is selected from the group consisting of —(SO 2 )R 2 , —(SO 2 )NR 2 R 3 , and —(CO)R 2 ; and

R 5 is aryl or heteroaryl, or R 4 and R 5 together with the atom to which they are attached form a heterocyclyl.

2. The method of claim 1 , wherein R a is H.

3. The method of claim 1 , wherein R 4 is —(SO 2 )R 2 .

4. The method of claim 3 , wherein —(SO 2 ) R 2 is —(SO 2 )alkyl, —(SO 2 )alkyleneheterocyclyl, —(SO 2 )haloalkyl, —(SO 2 )haloalkoxy, or —(SO 2 )cycloalkyl.

5. The method of claim 1 , wherein R 5 is heteroaryl.

6. The method of claim 5 , wherein the heteroaryl is a 5- to 6-membered heteroaryl selected from the group consisting of

wherein R b is halogen, alkyl, alkoxy, cycloalkyl, —CN, haloalkyl, or haloalkoxy; and m is 0 or 1.

7. The method of claim 6 , wherein R b is selected from the group consisting of F, Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CF 2 CH 3 , —CN, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —OCH 2 CF 2 H, and cyclopropyl.

8. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the method reduces left ventricular (LV) mass.

20. The method of claim 1 , wherein the method reduces LV wall thickness.

21. The method of claim 1 , wherein the method improves LV relaxation.

22. The method of claim 1 , wherein the method improves LV filling pressure.

23. The method of claim 1 , wherein the method reduces cardiac fibrosis.

24. The method of claim 1 , wherein the method reduces cardiac fibroblast activation in a cell.

25. The method of claim 1 , wherein the method reduces the expression of one or more genes associated with fibrosis.

26. The method of claim 1 , wherein the method reduces TGF-beta receptor signaling.

27. The method of claim 1 , wherein the method reduces cardiac muscle hypertrophy.

28. The method of claim 1 , wherein the HDAC6 inhibitor is a compound having the structure:

or a pharmaceutically acceptable salt thereof.

29. The method of claim 1 , wherein R 5 is aryl and the aryl is phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, or 2,6-difluorophenyl.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2023
From: YANG, JIN; MANDEGAR, MOHAMMAD A.; HOEY, TIMOTHY C.
To: TENAYA THERAPEUTICS, INC.
Reel/Frame 064504/0787 →
Continuity (5)
Continuation PCTUS2022027725 · May 4, 2022
Provisional Application 63210690 · Jun 15, 2021
Provisional Application 63210676 · Jun 15, 2021
Provisional Application 63183914 · May 4, 2021
Related Publication 20230381148A1 · Nov 30, 2023
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