Verticilide enantiomer and methods of inhibiting cardiac ryanodine receptor-mediated intracellular calcium release

Patent metadata

Field	Value
Publication number	US-11208435-B2
Application number	US-201816626073-A
Country	US
Kind code	B2
Filing date	Jun 25, 2018
Priority date	Jun 23, 2017
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The non-natural enantiomer (ent-(+)-verticilide) and uses for treatment of RyR2-mediated spontaneous Ca2+ leak, arrhythmia and memory loss.

First claim

We claim:

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A method for preventing, or ameliorating at least one of an atrial fibrillation, arrhythmia, or CPVT incident, comprising administering to a subject in need thereof an effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein said subject has been diagnosed with atrial fibrillation or arrhythmia.

5. The method of claim 3 , wherein said subject is at risk of persistent atrial fibrillation or arrhythmia.

6. The method of claim 3 , wherein said subject has had at least one prior incident of atrial fibrillation or arrhythmia.

7. The method of claim 6 , wherein said administering step reduces the likelihood of future incidents of atrial fibrillation or arrhythmia in said subject.

8. The method of claim 6 , wherein said administering reduces the likelihood of said atrial fibrillation or arrhythmia from becoming persistent or permanent.

9. The method of claim 3 , wherein said subject is a human.

10. A method of improving symptoms of memory loss associated with Alzheimer's disease in a subject in need thereof, comprising administering to said subject an effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein said subject is a human.

12. The method of claim 10 , wherein said subject has been diagnosed with Alzheimer's disease.

13. A method of improving symptoms of memory loss exacerbated by RyR2-mediated Ca 2+ leak in a subject in need thereof, comprising:
identifying a subject in need of stabilizing RyR2 and reducing Ca 2+ leak; and
administering to said subject an effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 , wherein said subject has been diagnosed with memory loss.

Assignees

• Univ Vanderbilt

Inventors

• Johnston Jeffrey N
• Batiste Suzanne
• Knollmann Bjorn C
• Blackwell Daniel J
• Gomez-Hurtado Nieves

Classifications

• C07K11/02 Primary

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07K11/00

  Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof · CPC title