RU2023103043A

RU2023103043A - IMPROVED PEPTIDE DRUGS FOR THE TREATMENT OF NASH AND OTHER DISORDERS

Info

Publication number: RU2023103043A
Application number: RU2023103043A
Authority: RU
Inventors: Джон Дж. НЕСТОР
Original assignee: Медерис Дайабетс, Ллк
Priority date: 2018-01-03
Filing date: 2019-01-03
Publication date: 2023-02-16

Claims

1. Use of a GLP1/glucagon peptide product or a pharmaceutically acceptable salt thereof for the treatment of fatty liver disease, said GLP1/glucagon peptide product having Formula I-A:

Formula IA,

where surfactant X is a moiety of Formula I:

Formula I

wherein:

R ^1a is independently at each occurrence a bond, H, a protecting group, a saccharide, an unsubstituted or substituted C ₁ C ₃₀ alkyl group, an unsubstituted or substituted aralkyl (-alkylaryl) group, an unsubstituted or substituted alkyloxyaryl group, or a group containing a steroid nucleus;

R ^1b , R ^1c and R ^1d are each independently a bond, H, a protecting group, a saccharide, an unsubstituted or substituted C ₁ C ₃₀ alkyl group, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted alkyloxyaryl group, or a group containing a steroid nucleus ;

R ² is a bond to U;

W ¹ in each case independently represents -CH ₂ -, -CH ₂ -O-, -CH ₂ -S-, -CH ₂ -NH-, -(C=O)-, -(C=O)-NH -, -(C=S)- or -(C=S)-NH-;

W ² is at each occurrence independently -O-, -S-, -NH- or -CH ₂ -;

and in at least one case, R ^1a , R ^1b , R ^1c , R ^1d or R ² represents an unsubstituted or substituted C ₁ C ₃₀ alkyl, aralkyl, alkyloxyaryl or a group containing a steroid nucleus;

and n is 1, 2 or 3; And

the peptide has Formula III-A:

aa ₁ -aa ₂ -aa ₃ -aa ₄ -aa ₅ -aa ₆ -aa ₇ -aa ₈ -aa ₉ -aa ₁₀ -aa ₁₁ -aa ₁₂ -aa ₁₃ -aa ₁₄ -aa ₁₅ -aa ₁₆ -aa ₁₇ -aa ₁₈ -aa ₁₉ -aa ₂₀ -aa ₂₁ -aa ₂₂ -aa ₂₃ -aa ₂₄ -aa ₂₅ -aa ₂₆ -aa ₂₇ -aa ₂₈ -aa ₂₉ -Z

Formula III-A (SEQ ID NO: 1110),

wherein:

Z is -OH or -NHR ³ where R ³ is H, unsubstituted or substituted C ₁ -C ₁₂ alkyl or a PEG-containing group of less than 10 Da;

aa ₁ is His ;

aa ₂ is Aib;

aa ₃ is Gln;

aa ₄ is Gly;

aa ₅ is Thr;

aa ₆ is Phe;

aa ₇ is Thr;

aa ₈ is Ser;

aa ₉ is Asp;

aa ₁₀ is Tyr, Glu, Lys or U(X);

aa ₁₁ is Ser;

aa ₁₂ is Lys or Glu;

aa ₁₃ is Tyr;

aa ₁₄ is Leu, Glu or Lys;

aa ₁₅ is Asp;

aa ₁₆ is Glu or Lys;

aa ₁₇ is Gln, Glu or U(X);

aa ₁₈ is Ala;

aa ₁₉ is Ala;

aa ₂₀ is Glu, Lys or U(X);

aa ₂₁ is Glu;

aa ₂₂ is Phe;

aa ₂₃ is Ile;

aa ₂₄ is Gln, Glu or U(X);

aa ₂₅ is Trp;

aa ₂₆ is Leu;

aa ₂₇ is Leu;

aa ₂₈ is Gln;

aa ₂₉ is Thr;

aa ₁₀ and aa ₁₄ or aa ₁₂ and aa ₁₆ or aa ₁₆ and aa ₂₀ are cyclized through their side chains to form a lactam bond; And

with the proviso that one or at least one of aa ₁₀ , aa ₁₇ , aa ₂₀ and aa ₂₄ is a natural or non-natural U amino acid covalently linked to a surfactant X.

2. Use according to claim 1, wherein the surfactant X contains a monosaccharide selected from glucuronic acid, galacturonic acid or mannuronic acid, or a disaccharide selected from melibiuronic acid, malturonic acid, isomalturonic acid, gentiobiuronic acid or lacturonic acid.

3. Use according to claim 1, wherein the surfactant X has the structure:

Formula I

wherein:

R ^1a is an unsubstituted or substituted C ₁ C ₃₀ alkyl group;

R ^1b , R ^1c and R ^1d are H;

R ² is a bond to U;

W ¹ represents -(C=O)-NH-; And

W ² is -O-.

4. Use according to claim 1, in which:

a) in at least one instance R ^1a is an unsubstituted or substituted C ₈ C ₂₀ alkyl group; or

b) Surfactant X is a 1-alkyl glycoside such as 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecyl beta- D-glucuronic acid, 1-dodecyl beta-D-glucuronic acid, 1-decyl beta-D-glucuronic acid, 1-octyl beta-D-glucuronic acid, 1-eicosyl beta-D-diglucuronic acid, 1-octadecyl-beta -D-diglucuronic acid, 1-hexadecyl beta-D-diglucuronic acid, 1-tetradecyl beta-D-diglucuronic acid, 1-dodecyl beta-D-diglucuronic acid, 1-decyl beta-D-diglucuronic acid, 1-octyl beta -D-diglucuronic acid, 1-eicosyl beta-D-isomalturonic acid, 1-octadecyl beta-D-isomalturonic acid, 1-hexadecyl beta-D-isomalturonic acid, 1-tetradecyl beta-D-isomalturonic acid, 1-dodecyl beta -D-isomalturonic acid, 1-decyl beta-D-isomalturonic acid, 1-octyl beta-D-isomalturonic acid, 1-eicosyl beta-D-gentiobiuronic acid, 1-octadecyl beta-D-gentiobiuronic acid, 1-hexadecyl beta-D-gentiobiuronic acid, 1-tetradecyl beta-D-gentiobiuronic acid, 1-dodecyl beta-D-gentiobiuronic acid, 1-decyl beta-D-gentiobiuronic acid, 1-octyl beta-D-gentiobiuronic acid, 1-eicosyl beta-D-melibiuronic acid, 1-octadecyl beta-D-melibiuronic acid, 1-hexadecyl beta-D-melibiuronic acid 1-tetradecyl beta-D-melibiuronic acid, 1-dodecyl beta-D-melibiuronic acid, 1-decyl beta-D-melibiuronic acid or 1-octyl beta-D-melibiuronic acid or functionalized 1-eicosyl beta-D-glucose, 1-octadecyl beta-D-glucose, 1-hexadecyl beta -D-glucose, 1-tetradecyl beta-D-glucose, 1-dodecyl beta-D-glucose, 1-decyl beta-D-glucose, 1-octyl beta-D-glucose, 1-eicosyl beta-D-maltoside, 1-octadecyl beta-D-maltoside, 1-hexadecyl beta-D-maltoside, 1-tetradecyl beta-D-maltoside, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, 1-octyl beta- D-maltoside, 1-eicosyl beta-D-melibioside, 1oc tadecyl beta-D-melibioside, 1-hexadecyl beta-D-melibioside, 1-tetradecyl beta-D-melibioside, 1-dodecyl beta-D-melibioside, 1-decyl beta-D-melibioside, or 1-octyl beta-D- melibioside or the corresponding 1-alkyl glycoside with a 6-carboxyl group or 6,6'-dicarboxyl groups or the corresponding 1-alkyl-alpha-anomer.

5. Application according to claim 1, in which

a) surfactant X is a 1-alkyl glycoside sulfactant; or

b) where aa ₁₇ Lys is covalently linked to a surfactant X, wherein the surfactant X is a 1-alkyl glycoside sulfactant.

6. Use according to claim 1, wherein said peptide product is His ₁ -Aib ₂ -Gln ₃ -Gly ₄ -Thr ₅ -Phe ₆ -Thr ₇ -Ser ₈ -Asp ₉ -Tyr ₁₀ -Ser ₁₁ -Lys ₁₂ -Tyr ₁₃ -Leu ₁₄ -Asp ₁₅ -Glu* ₁₆ -Lys(N-omega[1-(17-carboxy-heptadecyloxy) beta-D-glucuronyl]) ₁₇ -Ala ₁₈ -Ala ₁₉ -Lys* ₂₀ -Glu ₂₁ -Phe ₂₂ -Ile ₂₃ -Gln ₂₄ -Trp ₂₅ -Leu ₂₆ -Leu ₂₇ -Gln ₂₈ -Thr ₂₉ -NH ₂ (SEQ ID NO: 1119)

or a pharmaceutically acceptable salt thereof, wherein Glu ₁₆ * and Lys ₂₀ * denote residues that cyclize through their side chains to form a lactam bond.

7. The use of claim 1 wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD).

8. Use according to claim 1, wherein the fatty liver disease is non-alcoholic steatohepatitis (NASH).

9. Use according to claim 1, wherein the treatment comprises administering the peptide product via subcutaneous, intravenous, or intramuscular injection.

10. Use according to claim 1, wherein the treatment comprises administering the peptide product by oral inhalation or nasal inhalation or insufflation.

11. Use according to claim 9, wherein the administration of the peptide product is carried out at a dose of 0.1 to 1, 5 or 10 mg, or 0.1-1 mg, or 1-10 mg over a period of about one week.

12. The use according to claim 11, where the administration of the peptide product is carried out at a dose of 0.1-1 mg, or 0.1-0.5 mg, or 0.5-1 mg for about one week.

13. Use according to claim 9, wherein the treatment comprises administering the peptide product once a week.

14. Use according to claim 1, wherein the treatment further comprises administering one or more additional therapeutic agents.

15. The use of claim 14, wherein the one or more additional therapeutic agents are selected from antidiabetic agents, antiobesity agents, anti-inflammatory agents, antifibrotic agents, antioxidants, antihypertensive agents, and combinations thereof.

16. The use of claim 14 wherein the liver disease is NAFLD or NASH and the one or more additional therapeutic agents are selected from a peroxisome proliferator-activated receptor (PPAR) agonist, an HMG-CoA reductase inhibitor, a farnesoid X receptor (FXR) agonist or an antioxidant, or any combination thereof.

17. The use of a pharmaceutical composition for the treatment of fatty liver disease, while the drug is formulated for subcutaneous, intravenous or intramuscular injection, while the pharmaceutical composition contains:

a) a pharmaceutically acceptable diluent, carrier or excipient; And,

b) GLP1 peptide/glucagon covalently attached to surfactant X according to Formula I-A:

Formula IA

where surfactant X is a moiety of Formula I:

Formula I

Where:

R ² is a bond to U;

W ² is at each occurrence independently -O-, -S-, -NH- or -CH ₂ -;

and in at least one case, R ^1a , R ^1b , R ^1c , R ^1d or R ² represents an unsubstituted or substituted C ₁ C ₃₀ alkyl, aralkyl, alkyloxyaryl or a group containing a steroid nucleus; A

n is 1, 2 or 3; And

the GLP1/glucagon peptide is represented by Formula III-A:

aa ₁ -aa ₂ -aa ₃ -aa ₄ -aa ₅ -aa ₆ -aa ₇ -aa ₈ -aa ₉ -aa ₁₀ -aa ₁₁ -aa ₁₂ -aa ₁₃ -aa ₁₄ -aa ₁₅ -aa ₁₆ -aa ₁₇ -aa ₁₈ -aa ₁₉ -aa ₂₀ -aa ₂₁ -aa ₂₂ -aa ₂₃ -aa ₂₄ -aa ₂₅ -aa ₂₆ -aa ₂₇ -aa ₂₈ -aa ₂₉ -Z Formula III-A (SEQ ID NO: 1110)

Where:

Z is -OH or -NHR ³ where R ³ is H, unsubstituted or substituted alkyl C ₁ -C ₁₂ or a PEG-containing group of less than 10 Da;

aa ₁ is His;

aa ₂ is Aib;

aa ₃ is Gln;

aa ₄ is Gly;

aa ₅ is Thr;

aa ₆ is Phe;

aa ₇ is Thr;

aa ₈ is Ser;

aa ₉ is Asp;

aa ₁₀ is Tyr, Glu, Lys or U(X);

aa ₁₁ is Ser;

aa ₁₂ is Lys or Glu;

aa ₁₃ is Tyr;

aa ₁₄ is Leu, Glu or Lys;

aa ₁₅ is Asp;

aa ₁₆ is Glu or Lys;

aa ₁₇ is Gln, Glu or U(X);

aa ₁₈ is Ala;

aa ₁₉ is Ala;

aa ₂₀ is Glu, Lys or U(X);

aa ₂₁ is Glu;

aa ₂₂ is Phe;

aa ₂₃ is Ile;

aa ₂₄ is Gln, Glu or U(X);

aa ₂₅ is Trp;

aa ₂₆ is Leu;

aa ₂₇ is Leu;

aa ₂₈ is Gln;

aa ₂₉ is Thr;

18. The use of claim 17 wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).