# US 2023/0054976 A1 · METHODS FOR INHIBITION OF ALPHA-SYNUCLEIN mRNA USING SMALL MOLECULES

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- Number: US 2023/0054976 A1
- Document ID: US20230054976A1
- Status: Published application
- Kind: A1
- Application number: 17/757,609
- Filed: 2020-12-18
- Published: 2023-02-23
- Earliest claimed: 2019-12-19
- Assignees: The Scripps Research Institute; Rutgers, The State University of New Jersey
- Applicants: The Scripps Research Institute; Rutgers, The State University of New Jersey
- Inventors: Matthew David DISNEY; M. Maral MOURADIAN
- Web page: https://patentgrep.com/patent/US20230054976A1

## CPC

- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- C07D 403/14: containing three or more hetero rings
- A61P 25/16: Anti-Parkinson drugs
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A sequence-based design has provided a group of small molecules that target the IRE structure and inhibit SNCA translation in cells, which are named synucleozid compounds. The synucleozid compounds have a diphenyloxo- or diphenylamino-benzimidazole or indole core with various terminal amino or heterocycle groups as substituents.

## Claims

### Claim 1

A method for complexing an SNCA mRNA comprising contacting the SNCA mRNA with a synucleozid compound comprising Formula I
wherein:
Y is nitrogen or CR1
X is oxygen or NR2;
Z is hydrogen, methyl or
Im1 is guanidyl
imidazolyl, dihydroimidazolyl, imidazolinyl, pyrrolyl, pyrrolidinyl, or cyano;
Im2 is guanidyl, imidazolyl, dihydroimidazolyl, imidazolinyl, pyrrolyl, pyrrolidinyl, or cyano;
Im1 and Im2 are the same or different;
R1 and R2 are each independently hydrogen or methyl;
and a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A method according to claim 1 wherein the synucleozid compound of Formula I has Z as
so that Formula I comprises Formula II
wherein R2 is hydrogen and Im1 and Im2 are the same or different; and a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A method of claim 1 wherein the SNCA mRNA is in a mixture with other mRNA molecules.

### Claim 4

(canceled)

### Claim 5 (depends on 1)

A method of claim 1 wherein the SNCA mRNA is present in a cell.

### Claim 6 (depends on 5)

A method of claim 5 wherein the cell is in a cell culture

### Claim 7 (depends on 5)

A method of claim 5 wherein the cell is in living tissue.

### Claim 8 (depends on 2)

A method of claim 2 wherein the synucleozid compound is Formula II and Im1 and Im2 are each imidazolyl, dihydroimidazolyl, imidazolinyl, or guanidyl.

### Claim at position 9

-11. (canceled)

### Claim 12 (depends on 2)

A method of claim 2 wherein the synucleozid compound is Formula II and Y is N.

### Claim 13 (depends on 2)

A method of claim 2 wherein the synucleozid compound is Formula II and Y is CH.

### Claim 14 (depends on 2)

A method of claim 2 wherein the synucleozid compound is Formula II and X is O.

### Claim 15 (depends on 2)

A method of claim 2 wherein the synucleozid compound is Formula II and X is NH.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a pharmaceutical carrier and a synucleozid compound of Formula I of claim 1.

### Claim 17

(canceled)

### Claim 18 (depends on 1)

A method of claim 1 wherein the contacting step is an in vitro step with isolated mRNA.

### Claim 19 (depends on 1)

A method for treatment of a synucleinopathy disease comprising administration to a patient having the disease, an effective amount of a synucleozid compound of Formula I of claim 1.

### Claim 20

(canceled)

### Claim 21 (depends on 19)

A method for treatment according to claim 19 wherein the synucleinopathy disease is Parkinson's disease, Dementia with Lewy Bodies or Multiple System Atrophy.

### Claim 22 (depends on 21)

A method according to claim 21 wherein the disease is Parkinson's disease.

### Claim 23 (depends on 1)

A method for reducing or inhibiting production of α-synuclein protein by a cell carrying the SNCA gene comprising applying to the cell a synucleozid compound of Formula I of claim 1.

### Claim 24 (depends on 23)

A method according to claim 23 wherein the cell carrying the SNCA gene is present in living tissue.

### Claim 25 (depends on 24)

A method according to claim 24 wherein the living tissue is tissue of a mammalian animal.

### Claim 26

(canceled)

### Claim 27 (depends on 1)

A method for reducing or inhibiting translation of synuclein messenger RNA in an extracellular medium also containing ribosomes comprising contacting the medium with a synucleozid compound of Formula I of claim 1.

### Claim 28 (depends on 1)

A method for reducing or inhibiting translation of synuclein messenger RNA in a cell carrying the SNCA gene comprising contacting the cell with a synucleozid compound of Formula I of claim 1.

### Claim 29 (depends on 28)

A method of claim 28 wherein the cell carrying the SNCA gene is in a cellular culture.

### Claim 30 (depends on 28)

A method of claim 28 wherein the cell carrying the SNCA gene is in living tissue.

### Claim 31 (depends on 30)

A method of claim 30 wherein the living tissue is tissue of a mammalian animal.

### Claim 32

(canceled)

### Claim 33 (depends on 16)

A pharmaceutical composition of claim 16, wherein the synucleozid compound of Formula I is a synucleozid compound of Formula II
wherein
Y is nitrogen or CR1
X is oxygen or NR2;
Z is hydrogen, methyl or
Im1 is guanidyl
imidazolyl, dihydroimidazolyl, imidazolinyl, pyrrolyl, pyrrolidinyl, or cyano;
Im2 is guanidyl, imidazolyl, dihydroimidazolyl, imidazolinyl, pyrrolyl, pyrrolidinyl, or cyano;
Im1 and Im2 are the same or different;
R1 and R2 are each independently hydrogen or methyl;
and a pharmaceutically acceptable salt thereof.

### Claim 34 (depends on 33)

A composition according to claim 33 wherein Im1 and Im2 are the same.

### Claim 35 (depends on 2)

A method according to claim 2 wherein Im1 and Im2 are the same.