Novel Metabolic Disease Therapy

• US 20120053222A1
• Filed: 01/22/2010
• Published: 03/01/2012
• Est. Priority Date: 01/23/2009
• Status: Abandoned Application

• Current Assignee: Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney
• Original Assignee: Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney
• Inventors: Gorrell, Mark, Song, Sunmi, Wang, Xin
• Application Number:
  US13/145,906
• Publication Number:
  US 20120053222A1
• Time in Patent Office: Days
• US Class Current: 514/428
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: C07D 205/02 not condensed with other rings
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/06 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

The invention relates to the prevention and treatment of metabolic abnormalities characterized by abnormal glucose metabolism, including diabetes mellitus and new onset diabetes mellitus through the use of fibroblast activation protein (FAP) selective inhibitors.

Claims

1. Use of a FAP selective inhibitor for one or more of:

controlling blood glucose level;

increasing insulin secretion;

decreasing glucagon secretion;

increasing β

cell mass and insulin gene expression;

inhibiting acid secretion and gastric emptying in the stomach;

decreasing food intake by increasing satiety.

5. A method or use according to claim 1 wherein said FAP selective inhibitor does not substantially inhibit the dipeptidyl peptidase activity of DPIV.

6. The method or use according to claim 5 wherein said FAP selective inhibitor does not substantially inhibit the dipeptidyl peptidase activity of DP8, DP9 or PEP.

7. The method or use according to claim 1 wherein the inhibitor is selected from the group consisting of

(2S)-1-((2 S)-2-(2-Methoxybenzoylamino)-3-methylpentanoyl) pyrrolidine-2-carbonitrile;

(2S)-1-((2 S)-2-(Ethylcarbamoylamino)-3-methylpentanoyl) pyrrolidine-2-carbonitrile;

(2S)-1-((2 S)-2-(3-Methoxybenzoylamino)-3-methylpentanoyl) pyrrolidine-2-carbonitrile;

(2S)-1-(2-(N-Benzyl-N-(2-methoxybenzoyl) amino)acetyl)pyrrolidine-2-carbonitrile;

(2S)-1-(2-(2-Methoxybenzoylamino)-2-methyl propanoyl)pyrrolidine-2-carbonitrile;

(2S)-1-((2S)-2-(Ethylcarbamoylamino)-3-methylbutanoyl)pyrrolidine-2-carbonitrile;

(2S)-1-a2S)-2-(Isopropylcarbamoylamino)propanoyl)-pyrrolidine-2-carbonitrile;

(2S)-1-((2S)-2-(Ethylcarbamoyl)octahydroindole-2-carbonyl)pyrrolidine-2-carbonitrile;

(2S)-1-((2S)-2-(N-Ethylcarbamoyl-N-methylamino)-4-methylpentanoyl) pyrrolidine-2-carbonitrile;

(2S)-1-((2S)-2-(Benzylcarbamoylamino)-3, 3-dimethylbutanoyl)pyrrolidine-2-carbonitrile;

(2S)-1-((2S)-2-(Isopropylcarbamoylamino)-3-phenylpropanoyl)pyrrolidine-2-carbonitrile;

(2S)-1-((2S)-2-(Cyclohexylcarbamoylamino)-4-methylpentanoyl)pyrrolidine-2-carbonitrile; and

(2S)-1-((2S)-2-(Ethylcarbamoylamino)-3-methylpentanoyl)-3,4-dehydropyrrolidine-2-carbonitrile.

8. The method or use according to claim 1 wherein the inhibitor is selected from the group consisting of

(2S)-2-Formyl-1-((2S)-2-(2-methoxybenzoylamino)-3-methylbutanoyl)pyrrolidine;

(2S)-2-Formyl-1-((2S)-1-(3-methoxybenzoyl)pyrrolidine-2-carbonyl)pyrrolidine;

(2S)-2-Formyl-1-((2S)-1-(ethylcarbamoyl)octahydroindole-2-carbonyl)pyrrolidine;

(2S)-2-Formyl-1-((2S)-2-(2-methoxybenzoyl)-octahydroindole-2-carbonyl) pyrrolidine; and

(2S)-2-Formyl-1-(2S)-2-(2-methoxybenzoylamino)-3-phenylpropanoyl)pyrrolidine.

9. The method or use according to claim 1 wherein the inhibitor is a compound represented by Formula A:

10. The method or use according to claim 1 wherein the inhibitor is a compound represented by Formula B:

11. A kit for use in a method or use according to claim 1, the kit including:

a container holding a FAP selective inhibitor;

a label or package insert with instructions for use.

2. A method of preventing or treating one or more of the following diseases or conditions:

impaired glucose tolerance;

impaired fasting glucose;

insulin resistance;

new onset diabetes mellitus;

metabolic syndrome;

diabetes mellitus;

hepatic steatosis;

the method including providing a FAP selective inhibitor to an individual having one or more the above diseases or conditions, or to an individual susceptible for one or more of the above diseases or conditions.

3. The method of claim 2, wherein the individual susceptible for one or more of the above diseases or conditions has

a pre-diabetic state.

4. A use of a FAP selective inhibitor in the manufacture of a medicament for preventing or treating one or more of the diseases or conditions according to claim 2.