METHODS FOR INHIBITING MUSCLE ATROPHY

• US 20160243132A1
• Filed: 02/23/2016
• Published: 08/25/2016
• Est. Priority Date: 06/06/2011
• Status: Active Grant

• Current Assignee: US Department of Veterans Affairs (Government of the United States of America), The United States of America Represented by The Department of Veterans Affairs
• Original Assignee: University of Iowa Research Foundation
• Inventors: KUNKEL, Steven D., ADAMS, Christopher M., WELSH, Michael
• Granted Patent: US 10,137,136 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4365 the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 : not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/58 : containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/06 : Anabolic agents androgens A61P5/26
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C12Q 1/6809 : Methods for determination or identification of nucleic acids involving differential detection
• CPC Class Codes: C12Q 2600/136 : Screening for pharmacological compounds
• CPC Class Codes: G01N 2800/10 : Musculoskeletal or connective tissue disorders
• CPC Class Codes: G01N 2800/52 : Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/5023 : on expression patterns

Abstract

In one aspect, the invention relates to methods for treating muscle atrophy by providing to an animal in need thereof an effective amount of a compound. The compound can modulate the expression levels of multiple mRNA of a muscle atrophy signature. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Claims

1. A method of treating muscle atrophy in an animal comprising administering to the animal an effective amount of a compound selected from (A) a compound having a structure represented by a formula:

2. The method of claim 1, wherein the compound has the structure represented by a formula:

3. The method of claim 1, wherein the compound has the structure represented by a formula:

4. The method of claim 1, wherein the compound has the structure represented by a formula:

5. The method of claim 1, wherein the compound has the structure represented by a formula:

6. The method of claim 1, wherein the compound has the structure represented by a formula:

7. The method of claim 1, wherein the compound has the structure represented by a formula:

8. The method of claim 1, wherein the compound has the structure represented by a formula:

the compound has the structure represented by a formula;

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from (A) a compound having a structure represented by a formula:

10. A kit comprising a compound selected from (A) a compound having a structure represented by a formula:

11. A method for identifying a compound that inhibits muscle atrophy when administered in a therapeutically effective amount to a mammal in need of treatment thereof, the method comprising the steps of:

(i) selecting a candidate compound;

(ii) determining the effect of the candidate compound on a cell'"'"'s expression levels of a plurality of induced mRNAs and/or repressed mRNAs of a Muscle Atrophy Signature,

wherein the candidate compound is identified as suitable for muscle atrophy inhibition if;

(a) more than one of the induced mRNAs of the Muscle Atrophy Signature are down regulated, compared to expression levels of the induced mRNAs of the Muscle Atrophy Signature in the same type of cell in the absence of the candidate compound, and/or

(b) more than one of the repressed mRNAs of the Muscle Atrophy Signature are up regulated, compared to expression levels of the repressed mRNAs of the Muscle Atrophy Signature in the same type of cell in the absence of the candidate compound.

12. The method of claim 11, wherein the Muscle Atrophy Signature is determined according to steps comprising:

a) determining mRNA expression levels in a muscle cell undergoing muscle atrophy,

b) determining mRNA expression levels in a muscle cell not undergoing muscle atrophy,

wherein an mRNA is determined to be part of the Muscle Atrophy Signature if;

(a) the mRNA is up regulated in the muscle cell undergoing muscle atrophy compared to the muscle cell not undergoing muscle atrophy, or

(b) the mRNA is down regulated in the muscle cell undergoing muscle atrophy compared to the muscle cell not undergoing muscle atrophy.

13. (canceled)

14. A method of lowering blood glucose in an animal comprising administering to the animal an effective amount of a compound having a structure represented by a formula:

15. A method of lowering blood glucose in an animal comprising administering to the animal an effective amount of a compound having a structure represented by a formula:

16. A method of facilitating tissue formation in vitro, the method comprising administering to the tissue a compound of the formula:

(A) a compound having a structure represented by a formula;

17. A method of testing for performance enhancing use of a tacrine analog, naringenin analog, allantoin analog, conessine analog, tomatidine analog, hippeastrine/ungerine analog or betulinic acid analog in an animal, the method comprising:

(a) obtaining a biological test sample from the animal; and

(b) measuring the amount of a compound selected from

(A) a compound having a structure represented by a formula;

18. The method of claim 17, wherein the superphysiological amount is greater than 200 mg/kg.

19. The method of claim 17, wherein the animal is a mammal, fish or bird.

20. The method of claim 17, wherein the biological sample is blood, urine, saliva, hair, muscle, skin, fat, or breath.