# US 11,078,488 B2 · Fibrotic treatment

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- Number: US 11,078,488 B2
- Document ID: US11078488B2
- Status: Granted
- Kind: B2
- Application number: 16/984,996
- Filed: 2020-08-04
- Published: 2020-11-19
- Granted: 2021-08-03
- Earliest claimed: 2015-07-30
- Assignees: Monash University
- Applicants: Monash University
- Inventors: Siew Yeen Chai; Robert Widdop; Tracey Gaspari; Huey Wen Lee
- Web page: https://patentgrep.com/patent/US11078488B2

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 31/351: not condensed with another ring
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 31/4433: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- C12N 2310/14: interfering nucleic acids [NA]
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compositions, methods and kits for the treatment of fibrosis. In particular, the compositions, methods and kits are particularly useful, but not limited to, the treatment of cardiac fibrosis. The invention provides a method of treating fibrosis in an individual comprising administering an inhibitor of insulin-regulated aminopeptidase (IRAP), thereby treating fibrosis.

## Claims

### Claim 1

A method of treating steatosis in an individual comprising administering an inhibitor of insulin-regulated aminopeptidase (IRAP) thereby treating steatosis.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the steatosis is nonalcoholic fatty liver disease (NAFLD).

### Claim 3 (depends on 1)

The method according to claim 1, wherein the steatosis is alcoholic steatohepatitis (ASH).

### Claim 4 (depends on 1)

The method according to claim 1, wherein the steatosis is non-alcoholic steatohepatitis (NASH).

### Claim 5 (depends on 1)

The method according to claim 1, wherein the inhibitor of RAP directly inhibits the enzymatic activity of IRAP.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the inhibitor;
(i) binds to RAP;
(ii) binds to the active site of RAP; or
(iii) competes with a substrate of RAP for binding to RAP.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the inhibitor of RAP exhibits a Ki value of less than 1 mM, as determined by an assay of aminopeptidase activity or substrate degradation,
wherein the assay of amino peptidase activity comprises hydrolysis of the synthetic substrate L-Leucine 7-amido-4-methyl coumarin hydrochloride (Leu-MCA) monitored by release of the fluorogenic product MCA;
wherein the assay of substrate degradation is degradation of the peptide substrates CYFQNCPRG or YGGFL.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the inhibitor is selected from the group consisting of a small molecule, an antibody and a peptide.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the inhibitor has a structure according to Formula (I):
wherein
A is aryl, heteroaryl carbocyclyl or heterocyclyl, each of which may be optionally substituted, when R1 is NHCOR8;
or quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridyl, phthalazinyl or pteridinyl, each of which may be optionally substituted, when R1 is NR7R8, NHCOR8, N(COR8)2, N(COR7)(COR8), N═CHOR8 or N═CHR8;
X is O, NR′ or S, wherein R′ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R7 and R8 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, or R7 and R8, together with the nitrogen atom to which they are attached form a 3-8-membered ring which may be optionally substituted;
R2 is CN, CO2R9, C(O)O(O)R9, C(O)R9 or C(O)NR9R10 wherein R9 and R19 are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, each of which may be optionally substituted, and hydrogen; or R9 and R10 together with the nitrogen atom to which they are attached, form a 3-8-membered ring which may be optionally substituted;
R3-R6 are independently selected from hydrogen, halo, nitro, cyano alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, amino, acyl, acyloxy, carboxy, carboxyester, methylenedioxy, amido, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, carbocyclylthio, acylthio and azido, each of which may be optionally substituted where appropriate, or any two adjacent R3-R6, together with the atoms to which they are attached, form a 3-8-membered ring which may be optionally substituted; and
Y is hydrogen or C1-10alkyl,
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the inhibitor has the structure:

### Claim 11 (depends on 1)

The method according to claim 1, wherein the inhibitor is an interfering RNA.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the inhibitor has a structure according to Formula (II):
wherein
A is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted;
RA and RB are independently selected from hydrogen, alkyl and acyl;
R1 is selected from CN or CO2RC;
R2 is selected from CO2RC and acyl;
R3 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted; or
R2 and R3 together form a 5-6-membered saturated keto-carbocyclic ring:
wherein n is 1 or 2;
and which ring may be optionally substituted one or more times by C1-6alkyl; or
R2 and R3 together form a 5-membered lactone ring (a) or a 6-membered lactone ring (b)
wherein an optional double bond and R′ is alkyl;
RC is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the inhibitor has the structure:

### Claim 14 (depends on 1)

The method according to claim 1, wherein the inhibitor has a structure according to Formula (III):
wherein
R1 is H or CH2COOH; and
n is 0 or 1; and
m is 1 or 2; and
W is CH or N;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the inhibitor has the structure:

### Claim 16 (depends on 1)

The method according to claim 1, wherein the inhibitor has a structure according to any one of the following sequences:
Val-Tyr-Ile-His-Pro-Phe,
c[Cys-Tyr-Cys]-His-Pro-Phe,
and
c[Hcy-Tyr-Hcy]-His-Pro-Phe.

### Claim 17 (depends on 1)

A method according to claim 1, wherein the inhibitor has a structure according to:

### Claim 18

A method for improving heart function or decreasing infact area following ischemic-reperfusion injury in an individual, the method comprising administering an inhibitor of insulin-regulated aminopeptidase (IRAP) to the individual thereby improving heart function or decreasing infact area following ischemic-reperfusion injury.