DK2229407T3 - Nye insulinderivater med ekstremt forsinket tids-/virkningsprofil - Google Patents
Nye insulinderivater med ekstremt forsinket tids-/virkningsprofil Download PDFInfo
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- DK2229407T3 DK2229407T3 DK09701358.5T DK09701358T DK2229407T3 DK 2229407 T3 DK2229407 T3 DK 2229407T3 DK 09701358 T DK09701358 T DK 09701358T DK 2229407 T3 DK2229407 T3 DK 2229407T3
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- Prior art keywords
- arg
- glu
- asp
- lys
- exendin
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- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940043430 calcium compound Drugs 0.000 description 1
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- 229940038661 humalog Drugs 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
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- 150000002681 magnesium compounds Chemical class 0.000 description 1
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/102—Mutagenizing nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Physics & Mathematics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Claims (33)
1. Insulinanalogon med formel I
idet AO repræsenterer Arg; A5 repræsenterer Asp, Gin eller Glu; A15 repræsenterer Asp, Glu eller Gin; A18 repræsenterer Asp, Glu eller Asn; B-l repræsenterer Asp, Glu eller en aminogruppe; BO repræsenterer Asp, Glu eller en kemisk binding; Bl repræsenterer Asp, Glu eller Phe; B2 repræsenterer Asp, Glu eller Val; B3 repræsenterer Asp, Glu eller Asn; B4 repræsenterer Asp, Glu eller Gin; B29 repræsenterer Lys; B30 repræsenterer Thr; B31 repræsenterer Arg eller Lys; B32 repræsenterer Arg-NH2 eller Lys-NH2 idet to aminosyrerester fra gruppen indeholdende A5, A15, A18, B-l, BO, Bl, B2, B3 og B4 samtidigt og uafhængigt af hinanden repræsenterer Asp eller Glu.
2. Insulinanalogon ifølge et eller flere af de foregående krav, idet A5 repræsenterer Glu.
3. Insulinanalogon ifølge et eller flere af de foregående krav, idet A15 repræsenterer Glu.
4. Insulinanalogon ifølge et eller flere af de foregående krav, idet A18 repræsenterer Asp.
5. Insulinanalogon ifølge et eller flere af de foregående krav, idet B-l repræsenterer en aminogruppe.
6. Insulinanalogon ifølge et eller flere af de foregående krav, idet BO repræsenterer Glu.
7. Insulinanalogon ifølge et eller flere af de foregående krav, idet Bl repræsenterer Asp.
8. Insulinanalogon ifølge et eller flere af de foregående krav, idet B2 repræsenterer Val.
9. Insulinanalogon ifølge et eller flere af de foregående krav, idet B3 repræsenterer Asp.
10. Insulinanalogon ifølge et eller flere af de foregående krav, idet B4 repræsenterer Glu.
11. Insulinanalogon ifølge et eller flere af de foregående krav udvalgt af en gruppe indeholdende: Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15) , Asp (A18) , Gly (A21), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15) , Asp (A18) , Gly (A21), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu(A5), Glu (A15), Gly (A21), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His(A8), Glu (A5), Gly (A21), Asp (B3) , Arg (B31) , Arg (B32) - NH2 humaninsulin, Arg (AO), His(A8), Glu (A5), Gly (A21) , Asp (B3) , Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (B3) , Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3) , Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His(A8), Gly (A21), Asp (B3) , Glu (B4) , Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5) , Gly (A21), Glu (B4), Arg (B31) , Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5) , Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5) , Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5) , Gly (A21), Glu (BO), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15) , Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (BO), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (Al8),Gly (A21), Glu (BO), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (Bl), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A5) , Gly (A21), Asp (Bl), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (Bl), Arg (B31), Arg(B32) - NH2 humaninsulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (Bl), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (Bl), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (Bl), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Asp (Bl), Arg (B31), Arg (B32) - NH2 humaninsulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Asp (Bl), Arg (B31), Lys (B32) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Arg (B31) - NH2 humaninsulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Lys (B31) - NH2 humaninsulin.
12. Fremgangsmåde til fremstilling af et insulinanalogon ifølge et af kravene 1 til 11, idet der rekombinant fremstilles en forløber af insulinanalogonet, forløberen enzymatisk processeres til dobbeltkædet insulin, og der gennemføres en kobling med argininamid i nærvær af et enzym med trypsinaktivitet, og insulinanalogonet isoleres.
13. Anvendelse af et insulinanalogon ifølge et af kravene 1 til 11 til fremstilling af et medikament til behandling af diabetes mellitus.
14. Anvendelse af et insulinanalogon ifølge et af kravene 1 til 11 i en fremgangsmåde til fremstilling af et medikament til behandling af diabetes mellitus type I eller type II eller til terapeutisk understøttelse af beta-celleregenerationen.
15. Lægemiddel indeholdende et insulinanalog ifølge et af kravene 1 til 11 og/eller fysiologisk forligelige salte heraf.
16. Formulering af insulinanalogonet ifølge et af kravene 1 til 11, idet formuleringen foreligger i vandig form indeholdende det opløste insulinanalogon.
17. Formulering af insulinanalogonet ifølge et af kravene 1 til 11, idet formuleringen foreligger i form af pulver.
18. Formulering ifølge krav 17, idet insulinanalogonet ifølge et af kravene 1 til 11 er indeholdt i krystallin og/eller amorf form.
19. Formulering af insulinanalogonet ifølge et af kravene 1 til 11, idet formuleringen foreligger i form af en suspension.
20. Formulering af insulinanalogonet ifølge et af kravene 1 til 11, idet formuleringen desuden indeholder en kemisk chaperon.
21. DNA kodende for en præ-proinsulin af et insulinanalogon ifølge et af kravene 1 til 11.
22. Vektor indeholdende et DNA ifølge krav 21.
23. Ikke-human værtsorganisme indeholdende et DNA ifølge krav 21 eller en vektor ifølge krav 22.
24. Formulering ifølge et eller flere af kravene 16 til 20, hvori der endvidere også er indeholdt et glucagon-lignende peptid-1 (GLP1) eller et analogon eller derivat heraf eller exendin-3 eller -4 eller et analogon eller derivat heraf.
25. Formulering ifølge krav 24, hvori der endvidere er indeholdt exendin-4.
26. Formulering ifølge krav 24, hvori et analogon af exendin-4 udvælges af en gruppe indeholdende H-desPro36-exendin-4-Lys6-NH2, H-des (Pro36'37) -exendin-4-Lys4-NH2 og H-des (Pro36'37)-exendin-4-Lys5_NH2, eller et farmakologisk acceptabelt salt heraf.
27. Formulering ifølge krav 24, hvori et analogon af exendin-4 udvælges af en gruppe indeholdende desPro36 [Asp28] exendin-4 (1-39), desPro36 [IsoAsp28] exendin-4 (1-39), desPro36 [Met (O)14, Asp23] exendin-4 (1-39), desPro36 [Met (O)14, IsoAsp28] exendin-4 (1-39), desPro36 [Trp(02)25 Asp28] exendin-2 (1-39), desPro36 [Trp(02) 25, IsoAsp28] exendin-2 (1-39), desPro36 [Met (O) 14Trp (O2)25, Asp28] exendin-4 (1-39) og desPro36 [Met (0) 14Trp (02) 25, IsoAsp28] exendin-4 (1-39), eller et farmakologisk acceptabelt salt heraf.
28. Formulering ifølge krav 27, hvori der på C-terminiene af analoger af exendin-4 er tilføjet peptidet -Lys6-NH2.
29. Formulering ifølge krav 24, hvori der udvælges et analogon af exendin-4 af en gruppe indeholdende H-(Lys)6- des Pro36 [Asp28] exendin-4 (1-39)-Lys6-NH2 des Asp28Pro36, Pro37, Pro38 exendin-4 (1-39) -NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) -NH2, H-Asn-(Glu) 5 des Pro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) -NH2, des Pro35, Pro37, Pro38 [Asp28] exendin-4 (1-39) - (Lys) 6~NH2, H-(Lys)6- des Pro36, Pro37, Pro33 [Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H-Asn-(Glu) b- des Pro36, Pro37, Pro38 [Asp28] exendin-4 (1-39)-(Lys) 6-NH2, H- (Lys) s- des Pro36 [Trp(02) 25, Asp28] exendin-4 (1-39)-Lys6-NH2, H- des Asp28 Pro36, Pro37, Pro38 [Trp (02)2S] exendin-4 (l-39-NH2, H- (Lys) 6- des Pro36, Pro37, Pro38 [Trp(02) 25, Asp28] exendin-4 (1-
39) -NH2, H-Asn-(Glu) 5- des Pro36, Pro37, Pro38 [Trp(02) 25, Asp28] exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Trp(02) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6- des Pro36, Pro37, Pro38 [Trp(02) 25, Asp28] exendin-4 (1- 39) - (Lys) 5-NH2, H-Asn-(Glu) 5- des Pro36, Pro37, Pro38 [Trp(02) 25, Asp28] exendin-4 (1-39) - (Lys) S-NH2, H- (Lys) 6- des Pro36 [Met (O)14, Asp28] exendin-4 (1-39)-Lys6-NH2, des Met (O)14 Asp28 Pro36, Pro37, Pro38 exendin-4 (1-39) -NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met (O)14, Asp28] exendin-4 (1-39) -NH2, H-Asn-(Glu) 5- des Pro36, Pro37, Pro38 [Met (O)14, Asp28] exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Met (O)14, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met (O)14, Asp28] exendin-4 (1-39) -Lys6-NH2, H-Asn-(Glu) s des Pro36, Pro37, Pro38 [Met (O)14, Asp28] exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6~ des Pro36 [Met (O)14, Trp(02) 25, Asp28] exendin-4 (1-39) - LyS6-NH2, des Asp28 Pro36, Pro37, Pro38 [Met (O)14, Trp (02) 25] exendin-4 (1-39)-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met (O)14, Trp(02) 25, Asp28] exendin-4 (1-39) -NH2, H-Asn-(Glu) 5- des Pro36, Pro37, Pro38 [Met (O)14, Asp28] exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Met (O)14, Trp(02) 25, Asp28] exendin-4 (1- 39) - (Lys) 5-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met (O)14, Trp(02) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H-Asn-(Glu) b- des Pro36, Pro37, Pro38 [Met (O)14, Trp(02) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, eller et farmakologisk acceptabelt salt heraf.
30. Formulering ifølge krav 24, hvori der endvidere er indeholdt Arg34, Lys26 (Νε (γ-glutamyl (Na-hexadecanoyl) ) ) GLP-1 (7-37) [liraglutider] eller et farmakologisk acceptabelt salt heraf.
31. Vandig formulering af insulinanalogonet ifølge et af kravene 1 til 11, som indeholder ingen eller mindre end 15 pg/ml zink.
32. Vandig formulering af insulinanalogonet ifølge et af kravene 1 til 11, som indeholder ingen eller mindre end 15 yg/ml til 2 mg/ml zink.
33. Formulering ifølge krav 32, idet der er indeholdt 200 yg/ml zink.
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| DE200810003568 DE102008003568A1 (de) | 2008-01-09 | 2008-01-09 | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
| US4465908P | 2008-04-14 | 2008-04-14 | |
| DE200810025008 DE102008025008A1 (de) | 2008-05-24 | 2008-05-24 | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
| PCT/EP2009/000017 WO2009087081A2 (de) | 2008-01-09 | 2009-01-06 | Neue insulinderivate mit extrem verzögertem zeit-/wirkungsprofil |
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