DK2300035T3 - Blandede GIP-baserede agonister til behandling af metaboliske sygdomme og obesitet - Google Patents

Blandede GIP-baserede agonister til behandling af metaboliske sygdomme og obesitet Download PDF

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DK2300035T3
DK2300035T3 DK09800752.9T DK09800752T DK2300035T3 DK 2300035 T3 DK2300035 T3 DK 2300035T3 DK 09800752 T DK09800752 T DK 09800752T DK 2300035 T3 DK2300035 T3 DK 2300035T3
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glucagon
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Richard D Dimarchi
Tao Ma
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Univ Indiana Res & Tech Corp
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Claims (26)

1. Analog af glucagon (SEQ ID NO:1) med GIP-agonistaktivitet med følgende modifikationer: (a) en aminosyremodifikation i position 1, som medfører en GIP-agonistaktivitet, eventuelt hvor aminosyren i position 1 er en aminosyre, der mangler en imidazolsidekæde; (b) en, to, tre eller alle aminosyrer i position 16, 20, 21 og 24 af analogen er substitueret med en α,α-disubstitueret aminosyre, (c) aminosyremodifikationer i en, to eller alle positioner 27, 28 og 29 og (d) 1-9 yderligere aminosyremodifikationer i forhold til glucagonsekvensen (SEQ ID NO:1), hvor analogens EC50 for GIP-receptoraktivering er ca. 10 nM eller mindre, og hvor analogens EC50 ved GIP-receptoren er mindre end ca. 50 gange forskellig fra EC50 ved GLP-l-receptoren, eventuelt hvor analogens GIP-styrke er ca. 15 gange analogens GLP-1-styrke.
2. Analog af glucagon (SEQ ID NO:1) med GIP-agonistaktivitet med følgende modifikationer: (a) en aminosyremodifikation i position 1, som medfører en GIP-agonistaktivitet, eventuelt hvor aminosyren i position 1 er en aminosyre, der mangler en imidazolsidekæde, (b) en aminosyresubstitution af Ser i position 16 med en aminosyre med formel IV:
[formel IV], hvor n er 1 til 7, hvor hvert af R1 og R2 uafhængigt er udvalgt fra gruppen bestående af H, C1-C18 alkyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)NH2, (C1-C18 alkyl)SH, (C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyklisk), (C0-C4 alkyl)(C6-Cio aryl)R7 og (C1-C4 alkyl)(C3-C9 heteroaryl), hvor R7 er H eller OH, og sidekæden af aminosyren med formel IV omfatter en fri amino-gruppe, hvilken aminosyre med formel IV eventuelt er homoLys, Lys, Om eller 2,4-diaminobutansyre (Dab), (c) en aminosyresubstitution af Gin i position 20 med en alfa, alfa-disubstitueret aminosyre, eventuelt AIB, (d) aminosyremodifikationer i en, to eller alle positioner 27, 28 og 29 og (e) 1-9 yderligere aminosyremodifikationer i forhold til glucagonsekvensen (SEQ ID NO: 1), hvor analogens EC50 for GIP-receptoraktivering er ca. 10 nM eller mindre, og hvor analogens EC50 ved GIP-receptoren er mindre end ca. 50 gange forskellig fra EC50 ved GLP-l-receptoren, eventuelt hvor analogens GIP-styrke er ca. 15 gange analogens GLP-1-styrke.
3. Analog ifølge krav 1 eller 2, hvor (a) aminosyren i position 1 er en stor, aromatisk aminosyre, eventuelt Tyr, og (b) hvor (i) Met i position 27 er substitueret med en stor, alifatisk aminosyre, eventuelt Leu, (ii) Asn i position 28 er substitueret med en lille alifatisk aminosyre, eventuelt Ala, eller (iii) Thr i position 29 er substitueret med en lille alifatisk aminosyre, eventuelt Gly, eller hvor analogen omfatter en kombination af (i), (ii) og (iii).
4. Analog ifølge et af kravene 1-3, desuden omfattende aminosyresekvensen af GPSSGAPPPS (SEQ ID NO:95) eller XGPSSGAPPPS (SEQ ID NO:96) C-terminal til aminosyren i position 29.
5. Analog ifølge et af kravene 1-4, omfattende en eller flere af følgende modifikationer: (a) Ser i position 2, substitueret med D-Ser, Ala, D-Ala, Gly, N-methyl-Ser, AIB, Val eller a-amino-N-butansyre; (b) Gin i position 3, substitueret med Glu; (c) substitution af aminosyren Tyr i position 10 med en aminosyre, eventuelt en aminosyre med formel I:
hvor η = 1 til 4, omfattende en sidekæde, som er kovalent bundet til en acylgruppe eller al-kylgruppe; (d) tilsætning af en aminosyre, eventuelt en aminosyre med formel I, omfattende en sidekæde, som er kovalent bundet til en acylgruppe eller alkylgrup-pe som C-terminal-aminosyren af analogen; (e) Lys i position 12, substitueret med Ile; (f) Arg i position 17, substitueret med Gin; (g) Arg i position 18, substitueret med Ala; (h) Asp i position 21, substitueret med Glu; (i) Gin i position 24, substitueret med Asn; og (j) udskiftning af C-terminal-aminosyrens carboxylsyre med en ladningsneutral gruppe, eventuelt et amid.
6. Analog ifølge et af kravene 1-5, omfattende (a) en aminosyremodifikation i position 2, som yder modstand mod DPP-IV, og (b) en aminosyre i position 40, som er kovalent bundet til en acylgruppe eller alkylgruppe.
7. Analog ifølge et af kravene 1-6, omfattende en hydrofil enhed, som er bundet til en aminosyre i position 24.
8. Analog ifølge krav 2, omfattende aminosyresekvensen ifølge en af SEQ ID NO: 227, 228, 229 eller 230 og en udvidelse af 1 til 21 aminosyrer med C-terminal til aminosyren i position 29, eventuelt yderligere omfattende op til 6 yderligere aminosyremodifikationer.
9. Analog ifølge krav 8, hvor udvidelsen af 1 til 21 aminosyrer omfatter aminosyresekvensen af GPSSGAPPPS (SEQ ID NO:95) eller XGPSS-GAPPPS (SEQ ID NO:96), hvor X er en aminosyre eller en aminosyrese-kvens, der indeholder en eller flere konservative substitutioner i forhold til SEQ ID NO:95 eller 96.
10. Analog ifølge et af kravene 7-8, hvor mindst en af aminosyrerne med udvidelsen i en position, svarende til en af positionerne 37-43, eventuelt en aminosyre med formel I i position 40, er acetyleret eller alkyleret.
11. Analog ifølge krav 1, omfattende en aminosyresekvens udvalgt fra gruppen bestående af SEQ ID NO: 99-141, 144-164, 166, 192-207, 209-221 og 223.
12. Peptid bestående af aminosyresekvensen af SEQ ID NO:105.
13. Peptid bestående af aminosyresekvensen af SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 146 eller SEQ ID NO:153.
14. Peptid bestående af aminosyren af SEQ ID NO:1 med følgende aminosyremodifikationer:Tyr i position 1, en AIB i position 2, Lys i position 10, hvor Lys var kovalent bundet til en C16-fedtacylgruppe via en γ-Glu-y-Glu-dipeptidspacer, Ile i position 12, Lys i position 16, Gin i position 17, Ala i position 18, AIB i position 20, Glu i position 21, Asn i position 24, Leu i position 27, Ala i position 28, Gly i position 29, efterfulgt af aminosyren af SEQ ID NO:95 C-terminal til aminosyren i position 29 og et C-terminal-amid i stedet for C-terminal-alfa-carboxylatet.
15. Peptid, som omfatter aminosyresekvensen af SEQ ID NO: 105, hvor peptidets EC50 for GIP-receptoraktivering er ca. 10 nM eller mindre, og hvor peptidets EC50 ved GIP-receptoren er mindre end ca. 50 gange forskellig fra EC50 ved GLP-l-receptoren, eventuelt hvor peptidets GIP-styrke er ca. 15 gange peptidets GLP-1-styrke.
16. Peptid, som omfatter aminosyresekvensen af SEQ ID NO:107, SEQ ID NR:108, SEQ ID NR:109, SEQ ID NR: 146 eller SEQ ID NO:153, hvor peptidets EC50 for GIP receptoraktivering er ca. 10 nM eller mindre, og hvor peptidets EC50 ved GIP-receptoren er mindre end ca. 50 gange forskellig fra EC50 ved GLP-l-receptoren, eventuelt hvor peptidets GIP-styrke er ca. 15 gange peptidets GLP-1-styrke.
17. Peptid, som omfatter aminosyren af SEQ ID NO:1 med følgende aminosyremodifikationer:Tyr i position 1, en AIB i position 2, Lys i position 10, hvor Lys var kovalent bundet til en C16-fedtacylgruppe via en γ-Glu-Y-Glu-dipeptid-spacer, Ile i position 12, Lys i position 16, Gin i position
17. Ala i position 18, AIB i position 20, Glu i position 21, Asn i position 24, Leu i position 27, Ala i position 28, Gly i position 29, efterfulgt af aminosyren af SEQ ID NO:95 C-terminal til aminosyren i position 29 og et C-terminalamid i stedet for C-terminal-alfa-carboxylatet, hvor peptidets EC50 for GIP-receptoaktivering er ca. 10 nM eller mindre, og hvor peptidets EC50 ved GIP-receptoren er mindre end ca. 50 gange forskellig fra EC50 ved GLP-I-receptoren, eventuelt hvor peptidets GIP-styrke er ca. 15 gange peptidets GLP-1-styrke.
18. Analog ifølge krav 1-9, omfattende en acylgruppe eller alkylgruppe, som er bundet til aminosyresidekæden via en spacer, eventuelt hvor spaceren er 3 til 10 atomer i længden og er et dipeptid, eventuelt hvor spaceren omfatter to negativt ladede aminosyrer.
19. Analog ifølge krav 18, hvor acylgruppen er en C12- til C18-fedtacylgruppe, eventuelt en C14- eller C16-fedtacylgruppe.
20. Analog ifølge et af kravene 1-11 eller 18-19 eller peptid ifølge et af kravene 12-17, hvor analogen eller peptidet er kovalent bundet til en hydrofil enhed, eventuelt et polyethylenglycol (PEG) i en af aminosyrepositionerne 19, 20. 23, 24, 27, 32, 43 eller C-terminus, eventuelt hvor den hydrofile enhed er kovalent bundet til Lys, Cys, Orn, homocystein eller acetyl-phenylalanin.
21. Analog eller peptid ifølge krav 20, hvor PEG har en molekylvægt på ca. 20.000 dalton til ca. 40.000 dalton.
22. Konjugat, dimer eller fusionspeptid omfattende en analog ifølge et af kravene 1 -11 eller 18-21 eller peptid ifølge et af kravene 12-17 eller 20-21.
23. Farmaceutisk sammensætning omfattende anlaogen ifølge et af kravene 1-11 eller 18-21 eller peptid ifølge et af kravene 12-17 eller 20-21, konjugat, dimer eller fusionspeptid ifølge krav 22 eller en kombination deraf og en farmaceutisk acceptabel bærer.
24. Kit, som omfatter en farmaceutisk sammensætning ifølge krav 23 og et apparat til at indgive en patient den farmaceutiske sammensætning, eventuelt hvor apparatet omfatter en sprøjte, som omfatter den farmaceutiske sammensætning.
25. Analog ifølge et af kravene 1-11 eller 18-21 eller peptid ifølge et af kravene 12-17 eller 20-21 til anvendelse ved reduktion af vægtforøgelse eller fremkaldelse af vægttab eller anvendelse af en analog ifølge et af kravene 1-11 eller 18-21 eller peptid ifølge et af kravene 12-17 eller 20-21 ved fremstilling af et medikament til at reducere vægtforøgelse eller fremkalde vægttab.
26. Analog ifølge et af kravene 1-11 eller 18-21 eller peptid ifølge et af kravene 12-17 eller 20-21 til anvendelse ved behandling af diabetes eller anvendelse af en analog ifølge et af kravene 1-11 eller 18-21 eller peptidet ifølge et af kravene 12-17 eller 20-21 ved fremstilling af et medikament til behandling af diabetes.
DK09800752.9T 2008-06-17 2009-06-16 Blandede GIP-baserede agonister til behandling af metaboliske sygdomme og obesitet DK2300035T3 (da)

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US7327408P 2008-06-17 2008-06-17
US7817108P 2008-07-03 2008-07-03
US9044808P 2008-08-20 2008-08-20
US15134909P 2009-02-10 2009-02-10
PCT/US2009/047447 WO2010011439A2 (en) 2008-06-17 2009-06-16 Gip-based mixed agonists for treatment of metabolic disorders and obesity

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