AGENTS USEFUL FOR TREATING OBESITY, DIABETES AND RELATED DISORDERS

• US 20150216819A1
• Filed: 08/30/2013
• Published: 08/06/2015
• Est. Priority Date: 08/31/2012
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Ixchel Pharma LLC
• Inventors: Cortopassi, Gino, Tomilov, Alexey
• Granted Patent: US 9,750,705 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/702 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: G01N 2333/912 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: G01N 2440/14 phosphorylation
• CPC Class Codes: G01N 33/573 : for enzymes or isoenzymes
• CPC Class Codes: G01N 33/74 : involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

This invention provides methods of identifying agents useful to prevent, ameliorate or treat one or more symptoms of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, aging, metabolic syndrome, or other metabolic syndrome component diseases, and methods of employing the identified agents to prevent, reduce, delay or inhibit one or more symptoms of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, aging, metabolic syndrome, or other metabolic syndrome component diseases.

Claims

1. A method of treating or effecting prophylaxis of impaired insulin sensitivity, glucose tolerance or obesity, comprising administering to a subject having the impaired insulin sensitivity, glucose tolerance or obesity an effective regime of idebenone, SrcI-1, candesartan cilextil, sulfisoxazole acetyl, metformin hydrochloride, pyronaridine tetraphoshate, azaperone, acarbose, pefloxacine, cypermethrin, tripelennamine citrate, diperodon hydrochloride, aniracetam, fpa 124, methacycline hydrochloride, arctigenin, 10a, pyrithyldione, TBB, ornithine, 11e, 14e, BI 78D3, nitazoxanide, N-Acetyl-O-phosphono-Tyr-Glu-Glu-Ile-Glu, or a pharmaceutically acceptable salt thereof, thereby treating or effecting prophylaxis of the of impaired insulin sensitivity, glucose tolerance or obesity.

2. The method of claim 1, wherein the subject has type 2 diabetes.

3. The method of claim 1, wherein the subject has a body mass index of at least 30.

4. A method of treating or effecting prophylaxis of impaired insulin sensitivity or obesity, comprising administering to a subject having the impaired insulin sensitivity or obesity an effective regime of a Shc antagonist, thereby treating or effecting prophylaxis of the syndrome or disorder.

5. A method of treating or effecting prophylaxis of metabolic syndrome, comprising administering to a subject having or at risk of metabolic syndrome an effective regime of idebenone, SrcI-1, candesartan cilextil, sulfisoxazole acetyl, metformin hydrochloride, pyronaridine tetraphoshate, azaperone, acarbose, pefloxacine, cypermethrin, tripelennamine citrate, diperodon hydrochloride, aniracetam, fpa 124, methacycline hydrochloride, arctigenin, 10a, pyrithyldione, TBB, ornithine, 11e, 14e, BI 78D3, nitazoxanide, N-Acetyl-O-phosphono-Tyr-Glu-Glu-Ile-Glu, or a pharmaceutically acceptable salt thereof, thereby treating or effecting prophylaxis of the syndrome.

6. The method of claim 5, wherein the subject has diabetes type 2.

7. The method of claim 5, wherein the subject is obese.

8. The method of claim 5, wherein the subject has impaired insulin sensitivity and glucose tolerance.

9. The method of claim 5, wherein the subject has hyperglycemia.

10. The method of claim 5, wherein the subject has dyslipidemia.

11. The method of claim 5, wherein the subject has microalbuminuria.

12. A method of inhibiting aging, comprising administering to a subject an effective regime of idebenone, SrcI-1, candesartan cilextil, sulfisoxazole acetyl, metformin hydrochloride, pyronaridine tetraphoshate, azaperone, acarbose, pefloxacine, cypermethrin, tripelennamine citrate, diperodon hydrochloride, aniracetam, fpa 124, methacycline hydrochloride, arctigenin, 10a, pyrithyldione, TBB, ornithine, 11e, 14e, BI 78D3, nitazoxanide, N-Acetyl-O-phosphono-Tyr-Glu-Glu-Ile-Glu, or a pharmaceutically acceptable salt thereof, thereby inhibiting aging.

13. A method of screening a compound for an indication of an activity useful for treating impaired insulin sensitivity, glucose intolerance or obesity;

comprising

exposing cells to the compound and insulin;

determining phosphorylation status of Akt1 and Erk, e.g. phospho-Akt1 and phospho-Erk;

wherein an increased ratio of levels of phospho-Akt-1 over phospho-Erk relative to a control ratio provides an indication the compound has activity useful for treating impaired insulin sensitivity or obesity.

14. The method of claim 13, further comprising determining drug-dependent effects on mitochondrial physiology by measuring of oxygen consumption and proton production rates of cells employing the Seahorse machine.

15. The method of claim 13, further comprising determining drug-dependent effects on mitochondrial O₂ uptake using biosensor plates.

16. The method of claim 13, further comprising determining drug-dependent effects on mitochondria by assay of phospho-AMP kinase.

17. The method of claim 13, further comprising determining cytoxicity of drugs by tubulin polymerization assay.

18. The method of claim 13, further comprising screening the compound in an animal model of diabetes.

19. The method of claim 13, further comprising screening the compound in an animal model of obesity.