# US 2016/0354480 A1 · Activated neurotensin molecules and the uses thereof

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- Number: US 2016/0354480 A1
- Document ID: US20160354480A1
- Status: Published application
- Kind: A1
- Application number: 15/111,835
- Filed: 2015-01-19
- Published: 2016-12-08
- Earliest claimed: 2014-01-20
- Assignees: Vect-Horus; Centre National De La Recherche Scientifique
- Applicants: Vect-Horus; Centre National De La Recherche Scientifique
- Inventors: GUILLAUME JACQUOT; PASCALINE LECORCHE; MICHEL KHRESTCHATISKY
- Web page: https://patentgrep.com/patent/US20160354480A1

## CPC

- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 29/02: without antiinflammatory effect
- C07K 7/06: having 5 to 11 amino acids
- C07K 7/083: {Neurotensin}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to activated neurotensin, pharmaceutical compositions comprising the same, and the uses thereof. The compounds and compositions of the invention may be used e.g., to reduce body temperature, attenuate or halt seizures, reduce excitotoxicity, promote neuroprotection, reduce neuroinflammation and aberrant axonal sprouting or reduce pain.

## Claims

### Claim at position 1

1-19. (canceled)

### Claim 20

A compound comprising a neurotensin polypeptide covalently coupled to an activator group, the activator group comprising the amino acid sequence M-aa1-R-L-R wherein aa1 is Proline or an analog thereof.

### Claim 21 (depends on 20)

The compound of claim 20, wherein the neurotensin polypeptide comprises (i) SEQ ID NO: 1; or (ii) a natural variant of (i); or (iii) a fragment of (i) or (ii); or (iv) an analog of any sequence of (i) to (iii), said polypeptide having a biological activity of neurotensin.

### Claim 22 (depends on 22)

The compound of claim 22, wherein the neurotensin polypeptide comprises SEQ ID NO: 2 or an analog thereof having a biological activity of neurotensin.

### Claim 23 (depends on 20)

The compound of claim 20, wherein the neurotensin polypeptide is selected from NT, NT(2-13), NT(6-13), and NT(8-13).

### Claim 24 (depends on 20)

The compound of claim 20, wherein the neurotensin polypeptide comprises a substitution or modification of 1, 2, 3, 4, 5, 6, or 7 amino acid residues.

### Claim 25 (depends on 20)

The compound of claim 20, wherein the neurotensin polypeptide is selected from [Lys8]NT(8-13), [Lys9]NT(8-13), [(D)-Lys8]NT(8-13), [(D)-Orn9]NT(8-13), [Lys8-Lys9]NT(8-13), [(D)-Lys8-Lys9]NT(8-13), [Trp11]NT(8-13), [neoTrp11]NT(8-13), [Tle12]NT(8-13), [Trp11,Tle12]NT(8-13), [neoTrp11,Tle12]NT(8-13), [Lys8, Tle12]NT(8-13), [(D)-Lys8,Tle12]NT(8-13), [(D)-Lys8,Trp11]NT(8-13), [(D)-Lys8,neoTrp11]NT(8-13), [Lys8, Trp11, Tle12]NT(8-13), [(D)-Lys8,Trp11,Tle12]NT(8-13), [(D)-Lys8,neoTrp11,Tle12]NT(8-13), [(D)-Lys8,Lys9,Trp11,Tle12]NT(8-13), [(D)-Lys8,Lys9,neoTrp11,Tle12]NT(8-13), [Lys9,Tle12]NT(8-13), [Lys9,Trp11]NT(8-13), [Lys9,neoTrp11]NT(8-13), [Lys9,Trp11,Tle12]NT(8-13), [Lys9,neoTrp11,Tle12]NT(8-13), [HLys8,Tle12]NT(8-13), [HLys8,Trp11]NT(8-13), [HLys8,neoTrp11]NT(8-13), [HLys8,Trp11,Tle12]NT(8-13), [HLys8,neoTrp11,Tle12]NT(8-13), [(D)-Orn9,Tle12]NT(8-13), [(D)-Orn9,Trp11]NT(8-13), [(D)-Orn9,neoTrp11]NT(8-13), [(D)-Orn9,Trp11,Tle12]NT(8-13), or [(D)-Orn9,neoTrp11,Tle12]NT(8-13).

### Claim 26 (depends on 20)

The compound of claim 20, wherein the activator group comprises any one of SEQ ID NOs: 5-11.

### Claim 27 (depends on 20)

The compound of claim 20, wherein the activator group and neurotensin polypeptide are conjugated through a linker group.

### Claim 28 (depends on 27)

The compound of claim 27, wherein the linker group comprises a polyethyleneglycol, a polyGly, an Ahx spacer group or a peptide bond.

### Claim 29 (depends on 20)

The compound of claim 20, which comprises a neurotensin polypeptide comprising SEQ ID NO: 2 or an analog thereof conjugated to an activator group comprising any one of SEQ ID NOs: 5-11, optionally through a linker group.

### Claim 30 (depends on 20)

The compound of claim 20, which comprises a neurotensin polypeptide comprising SEQ ID NO: 2 or an analog thereof conjugated to an activator group comprising any one of SEQ ID NOs: 5-11, by means of a peptide bond.

### Claim 31

A compound selected from compounds I to XX as listed in Table A.

### Claim 32 (depends on 20)

A pharmaceutical composition comprising a compound as defined in claim 20 and a pharmaceutically acceptable carrier or excipient.

### Claim 33 (depends on 20)

A method of making a compound comprising covalently coupling a neurotensin polypeptide to an activator group as defined in claim 20.

### Claim 34 (depends on 20)

A method for reducing body temperature in a mammalian subject comprising administering to the subject a compound as defined in claim 20 or a composition thereof to said subject.

### Claim 35 (depends on 34)

The method of claim 34, wherein hypothermia is induced in a mammalian subject following sudden cardiac arrest, or having a stroke, neonatal ischemia, heart surgery, traumatic head or spinal cord injury, seizures, pain or hyperthermia.

### Claim 36 (depends on 20)

A method for protecting against or for reducing brain damage in a mammalian subject comprising administering to the subject a compound as defined in claim 20 or a composition thereof to said subject.

### Claim 37 (depends on 20)

A method for reducing convulsions in a mammalian subject comprising administering to the subject a compound as defined in claim 20 or a composition thereof to said subject.

### Claim 38 (depends on 20)

A method for reducing pain in a mammalian subject comprising administering to the subject a compound as defined in claim 20 or a composition thereof to said subject.

### Claim 39 (depends on 31)

A pharmaceutical composition comprising a compound as defined in claim 31 and a pharmaceutically acceptable carrier or excipient.

### Claim 40 (depends on 31)

A method for reducing body temperature in a mammalian subject comprising administering to the subject a compound as defined in claim 31 or a composition thereof to said subject.

### Claim 41 (depends on 40)

The method of claim 40, wherein hypothermia is induced in a mammalian subject following sudden cardiac arrest, or having a stroke, neonatal ischemia, heart surgery, traumatic head or spinal cord injury, seizures, pain or hyperthermia.

### Claim 42 (depends on 31)

A method for protecting against or for reducing brain damage in a mammalian subject comprising administering to the subject a compound as defined in claim 31 or a composition thereof.

### Claim 43 (depends on 31)

A method for reducing convulsions in a mammalian subject comprising administering to the subject a compound as defined in claim 31 or a composition thereof.

### Claim 44 (depends on 31)

A method for reducing pain in a mammalian subject comprising administering to the subject a compound as defined in claim 31 or a composition thereof.