ES2672880T3 - Péptidos de la superfamilia de glucagón que muestran actividad de receptor de glucocorticoides - Google Patents
Péptidos de la superfamilia de glucagón que muestran actividad de receptor de glucocorticoides Download PDFInfo
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- ES2672880T3 ES2672880T3 ES12849285.7T ES12849285T ES2672880T3 ES 2672880 T3 ES2672880 T3 ES 2672880T3 ES 12849285 T ES12849285 T ES 12849285T ES 2672880 T3 ES2672880 T3 ES 2672880T3
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- 230000021615 conjugation Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 108700023159 delta Opioid Receptors Proteins 0.000 description 1
- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 108091008559 estrogen-related receptor alpha Proteins 0.000 description 1
- 108091008558 estrogen-related receptor beta Proteins 0.000 description 1
- 108091008557 estrogen-related receptor gamma Proteins 0.000 description 1
- 108020004067 estrogen-related receptors Proteins 0.000 description 1
- 108010067742 gamma nerve growth factor Proteins 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 108091008581 nuclear androgen receptors Proteins 0.000 description 1
- 108091008584 nuclear progesterone receptors Proteins 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- 108091008695 photoreceptors Proteins 0.000 description 1
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- RVEZZJVBDQCTEF-UHFFFAOYSA-N sulfenic acid Chemical compound SO RVEZZJVBDQCTEF-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- GSSFQJXXMLNLGH-YGYANBGASA-L zinc (2R)-2-amino-3-hydroxy-3-oxopropane-1-thiolate hydron Chemical compound [Zn++].N[C@@H](CS)C(O)=O.N[C@@H](CS)C(O)=O.N[C@@H](CS)C([O-])=O.N[C@@H](CS)C([O-])=O GSSFQJXXMLNLGH-YGYANBGASA-L 0.000 description 1
Classifications
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- 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
- C07K14/605—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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
- A61K47/54—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 compound
- A61K47/554—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 compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- A61P3/06—Antihyperlipidemics
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/71—Fusion polypeptide containing domain for protein-protein interaction containing domain for transcriptional activaation, e.g. VP16
- C07K2319/715—Fusion polypeptide containing domain for protein-protein interaction containing domain for transcriptional activaation, e.g. VP16 containing a domain for ligand dependent transcriptional activation, e.g. containing a steroid receptor domain
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Abstract
Compuesto que comprende la estructura Q-L-Y; en el que Q es un péptido de la superfamilia del glucagón; y en el que L-Y comprende la estructura (I):**Fórmula** en la que 20 L está unido a una cadena lateral que contiene amino o tiol de un aminoácido de Q correspondiente a la posición 40 de un análogo de glucagón natural modificado para comprender una extensión C-terminal de GPSSGAPPPS (SEQ ID NO: 1610), en el que dicha extensión C-terminal representa las posiciones de aminoácidos 30-39; o**Fórmula** en la que L está unido a una cadena lateral que contiene tiol de un aminoácido de Q correspondiente a la posición 40 de un análogo de glucagón natural modificado para comprender una extensión C-terminal de GPSSGAPPPS (SEQ ID NO: 1610), en el que dicha extensión C-terminal representa las posiciones de aminoácidos 30-39, e y es alquileno C1- C10, y dicho compuesto comprende la estructura**Fórmula**
Description
5
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35
40
en la que Q es osteocalcina, calcitonina, amilina, o un análogo, derivado o conjugado de los mismos, en lugar de un péptido de la superfamilia de glucagón; Y es un ligando de GR; y L es un grupo de unión o un enlace. En algunas realizaciones, Q comprende osteocalcina (SEQ ID NO: 1644), o una secuencia de aminoácidos que es al menos aproximadamente 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 %, 85%, 90% o 95% idéntica a la osteocalcina natural sobre la longitud del péptido natural. Q puede comprender un análogo de la osteocalcina con hasta 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10 modificaciones de aminoácidos en relación con la osteocalcina natural, o un análogo truncado de osteocalcina (por ejemplo, aminoácidos 70-84) con hasta 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10 modificaciones de aminoácidos en relación con la osteocalcina truncada natural. En algunas realizaciones, Q comprende calcitonina (SEQ ID NO: 1645), o una secuencia de aminoácidos que es al menos aproximadamente 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 %, 85%, 90% o 95% idéntica a calcitonina natural sobre la longitud del péptido natural. Q puede comprender un análogo de calcitonina con hasta 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10 modificaciones de aminoácidos con respecto a la calcitonina natural. En algunas realizaciones, Q comprende amilina (SEQ ID NO: 1646), o una secuencia de aminoácidos que es al menos aproximadamente 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 %, 85%, 90% o 95% idéntica a la amilina natural sobre la longitud del péptido natural. Q puede comprender un análogo de amilina con hasta 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10 modificaciones de aminoácidos con respecto a la amilina natural.
El ligando de GR (Y)
[0082] En la presente divulgación con respecto a los conjugados Q-L-Y, Y es un ligando que actúa en un receptor de glucocorticoides. Los receptores nucleares de hormonas, tales como GR, incluyen al menos uno de dominio de unión a ADN (DBD) de dedo de zinc de tipo C4 y/o un dominio de unión a ligando (LBD). El DBD funciona para unirse al ADN en la vecindad de los genes diana, y el LBD se une y responde a su hormona afín. "Receptores de hormonas nucleares clásicos" poseen un DBD y un LBD (por ejemplo, receptor de estrógenos alfa), mientras que otros receptores nucleares de hormonas poseen solamente un DBD (por ejemplo Knirps, ORD) o sólo un LBD (por ejemplo, short heterodimer partner (SHP)).
[0083] Los receptores nucleares de hormonas se pueden dividir en cuatro clases mecanísticas: Tipo I, Tipo II, Tipo III y Tipo IV. La unión del ligando a los receptores de Tipo I (grupo NR3) da como resultado la disociación de las proteínas de choque térmico (HSP) del receptor, la homodimerización del receptor, la translocación desde el citoplasma hacia el núcleo de la célula, y la unión a elementos de respuesta hormonal de repetición invertida (HRE) de ADN. El complejo receptor nuclear/ADN recluta a continuación otras proteínas que transcriben el ADN aguas abajo de los HRE en ARN mensajero. Los receptores de tipo II (grupo NR1) son retenidos en el núcleo y se unen como heterodímeros, generalmente con receptores de Retinoide X (RXR), al ADN. Los receptores nucleares de hormonas de tipo II son a menudo complejos con proteínas corepresoras. La unión de ligando al receptor de tipo II provoca la disociación del corepresor y el reclutamiento de las proteínas coactivadoras. Se reclutan proteínas adicionales para el complejo receptor nuclear/ADN que transcriben ADN en ARN mensajero. Los receptores nucleares de hormonas de Tipo III (grupo NR2) son receptores huérfanos que se unen a HRE de repetición directa de ADN como homodímeros. Los receptores nucleares de hormonas de Tipo IV se unen al ADN como monómeros o dímeros. Los receptores de Tipo IV son únicos porque un único dominio de unión al ADN del receptor se une a un único HRE de medio sitio. El ligando de NHR puede ser un ligando que actúa en uno cualquiera o más de receptores nucleares de hormonas de Tipo I, Tipo II, Tipo III o Tipo IV (por ejemplo, como un agonista o antagonista).
Tabla 1. Superfamilia de receptores nucleares de hormonas
- Receptor nuclear de hormona
- Especie Acceso Ligando endógeno
- Grupo NR1
- NR1A1
- Receptor alfa de hormona tiroides (TRα) Humana M24748 Hormona tiroides
- NR1A2
- Receptor beta de hormona tiroides (TRβ) Humana X04707
- NR1B1
- Receptor alfa de ácido retinoico (RARα) Humana X06538 Vitmaina A y compuestos relacionados
- NR1B2
- Receptor beta de ácido retinoico (RARβ) Humana Y00291
- NR1B3
- Receptor gamma de ácido retinoico (RARγ) Humana M57707
- NR1C1
- Receptor alfa activado por proliferadores de proxisoma (PPARα) Humana L02932 Ácidos grasos, prostaglandinas
- NR1C2
- Receptor beta/delta activado por proliferadores de proxisoma (PPARβ/δ) Humana L07592
- NR1C3
- Receptor gamma activado por proliferadores de proxisoma (PPARγ) Humana L40904
15
- NR1D1
- Rev-ErbAα Humana M24898 Hemoglobina
- NR1D2
- Rev-ErbAβ Humana L31785
- NR1F1
- Receptor alfa huérfano relacionado con RAR (RORα) Humana U04897 Colesterol, ácido retinoico todo-trans
- NR1F2
- Receptor beta huérfano relacionado con RAR (RORβ) Humana Y08639
- NR1F3
- Receptor gamma huérfano relacionado con RAR (RORγ) Humana U16997
- NR1H2
- Receptor X hepático beta (LXRβ) Humana U07132 Oxisterol
- NR1H3
- Receptor X hepático alfa (LXRα) Humana U22622
- NR1H4
- Receptor X farnesoide (FXR) Humana U68233
- NR1I1
- Receptor de vitamina D (VDR) Humana J03258 Vitamina D
- NR1I2
- Receptor X de pregnano Humana AF061056 Xenobióticos (dexametasona, rifapicina)
- NR1I3
- Receptor alfa constitutivo de androstano Humana Z30425 Androstano
- Grupo NR2
- NR2A1
- Factor nuclear 4 alfa de hepatocito (HNF4α) Humana X76930 Ácidos grasos
- NR2A3
- Factor nuclear 4 gamma de hepatocito (HNF4γ) Humana Z49826 Ácidos grasos
- NR2B1
- Receptor X retinoide alfa (RXRα) Humana X52773 Retinoides
- NR2B2
- Receptor X retinoide beta (RXRβ) Humana M84820
- NR2B3
- Receptor X retinoide gamma (RXRγ) Humana U38480
- NR2C1
- Receptor 2 testicular (TR2) Humana M29960
- NR2C2
- Receptor 4 testicular (TR4) Humana L27586
- NR2E1
- Homólogo humano del gen tailess de Drosophila (TLX) Humana Y13276
- NR2E3
- Receptor nuclear específico de fotoreceptor (PNR) Humana AF121129
- NR2F1
- Factor de transcripción I del promotor en dirección 5’ de la ovoalbúmina de pollo (COUP-TFI) Humana X12795
- NR2F2
- Factor de transcripción II del promotor en dirección 5’ de la ovoalbúmina de pollo (COUP-TFII) Humana M64497
- NR2F6
- Gen relacionado con V-erAA Humana X12794
- Grupo NR3
- NR3A1
- Receptor alfa de estrógeno (ERα) Humana P03372 Estrógeno
- NR3A2
- Receptor beta de estrógeno (ERβ) Humana AB006590
- NR3B1
- Receptor alfa relacionado de estrógeno (ERRα) Humana X51416
- NR3B2
- Receptor beta relacionado de estrógeno (ERRβ) Humana AF094517
- NR3B3
- Receptor gamma relacionado de estrógeno (ERRγ) Humana AF058291
- NR3C1
- Receptor glucocorticoide (GR) Humana X03225 Cortisol
- NR3C2
- Receptor mineralocorticoide (MR) Humana M16801 Aldosterona
- NR3C3
- Receptor de progesterona (PR) Humana M15716 Progesterona
- NR3C4
- Receptor de andrógeno (AR) Humana M20132 Testosterona
- Grupo NR4
- NR4A1
- Factor IB alfa del factor de crecimiento nervioso (NGFI-Bα) Humana L13740
- NR4A2
- Factor IB beta del factor de crecimiento nervioso (NGFI-Bβ) Humana X75918
- NR4A3
- Factor IB gamma del factor de crecimiento nervioso (NGFI-Bγ) Humana D78579
- Grupo NR5
- NR5A1
- Factor 1 esteroidogénico (SF1) Humana U76388
- NR5A2
- Homólogo 1 de receptor hepático Humana U93553
16
- 5
- [E9, E16K20 (lactama), D28] G(4 ~ 29) GTFTSEYSKYLDERRAKDFVQWLMDT 151 10 ~ 30
- 6
- [E9, E16K20 (lactama), D28] G(2 ~ 29) SQGTFTSEYSKYLDERRAKDFVQWLMDT 203 49 (PA)
- 7
- [A2E3, E16K20 (lactama), D28 ] G(2 ~ 29) AEGTFTSEYSKYLDERRAKDFVQWLMDT 175 63
- 8
- [A2E3, E16K20 (lactama), D28] G (1 ~ 29) HAEGTFTSEYSKYLDERRAKDFVQWLMDT 0,2 130 (PA)
- 9
- ANK2 (péptido Bayer) HSQGTFTSDY ARYLDARRAREFIKWL VRGRG 0,28 agonista
- *EC50 en el receptor de glucagón
Tabla 15: Perfil de agonista/antagonista mixto
- Análogos de glucagón (6-CEX)
- 1
- E9, K12, E16 FTSEYSKYLDERRAQDFVQWLMNTGPSSGAPPPS 1451 762
- 2
- E9, K12E16 (lactama) FTSEYSKYLDERRAQDFVQWLMNTGPSSGAPPPS 63 2008
- 3
- E9, E16K20 (lactama) FTSEYSKYLDERRAKDFVQWLMNTGPSSGAPPPS 36 42
- 4
- D9, K12E20 (lactama) FTSDYSKYLDERRAQDFVQWL1MNTGPSSGAPPPS 18 828
- 5
- [PLA6, E9, K12E20 (lactama) PLA TSEYSKYLDERRAQDFVQWLMNTGPSSGAPPPS 6 72
- 6
- [PLA6, E9, E16K20 (lactama)] PLA-TSEYSKYLDERRAKDFVQWLMNTGPSSGAPPPS 20 20
- Análogos de glucagón D9(6-29)
- GLP-1 EC50 (nM)
- Glucagón IC50 (nM)
- 7
- PLA 6, D9, D28 PLA-TSDYSKYLDSRRAQDFVQWLMDT -700 tbd
- 8
- PLA6, D9, K12E20 (lactama) PLA-TSDYSKYLDERRAQDFVQWLMDT 21 13
- 9
- PLA6, D9, E16K20 (lactama) PLA-TSDYSKYLDERRAKDFVQWLMDT 4 6
5 [0675] En algunas realizaciones, el péptido que comprende la estructura general A-B-C es un péptido de Clase 5. En una realización específica, el péptido muestra al menos aproximadamente 50% del agonismo máximo conseguido por GLP-1 natural en el receptor de GLP-1 y al menos una inhibición de aproximadamente 50% de la respuesta máxima conseguida por glucagón natural en el receptor de glucagón. En otra realización específica, el péptido
10 muestra al menos aproximadamente 55%, al menos aproximadamente 60%, al menos aproximadamente 70%, al menos aproximadamente 80%, al menos aproximadamente 90%, al menos aproximadamente 95%, o aproximadamente 100% del agonismo máximo conseguido por GLP-1 natural en el receptor de GLP-1. Alternativa o adicionalmente, el péptido puede mostrar al menos aproximadamente 55%, al menos aproximadamente 60%, al menos aproximadamente 70%, al menos aproximadamente 80%, al menos aproximadamente 90%, al menos
15 aproximadamente 95%, o aproximadamente el 100% de inhibición de la respuesta máxima conseguida por glucagón natural en el receptor de glucagón.
[0676] En algunas realizaciones, se proporciona un péptido de la clase 5 o conjugado del mismo, que comprende:
(1) las modificaciones que confieren actividad agonista de glucagón, incluyendo, pero no limitado a:
20 (a) sustitución de la Phe en la posición 6 con PLA ( según la numeración de los aminoácidos del glucagón de tipo natural), opcionalmente con la supresión de 1 a 5 aminoácidos de la N-terminal de glucagón de tipo natural; o
(b) la supresión de 2 a 5 aminoácidos del extremo N-terminal de glucagón de tipo natural; opcionalmente con sustitución de Asp en la posición 9 de glucagón de tipo natural con ácido glutámico, ácido homoglutámico o un derivado de ácido sulfónico de la cisteína (según la numeración de aminoácidos del glucagón de tipo natural); y
25 (2) las modificaciones que confieren GLP-1 actividad agonista, incluyendo, pero no limitado a:
(a) inserción o sustitución de alfa, alfa aminoácido disustituida dentro de los aminoácidos 12-29 de glucagón de tipo natural, por ejemplo en uno, dos, tres, cuatro o más de las posiciones 16, 17, 18, 19, 20, 21, 24 o 29 (según la numeración de aminoácidos del glucagón de tipo natural); o
118
- Ambos nucleófilos
- Ambos electrófilos Nucleófilo/electrófilo
- A
- B A B A B
- amino
- amino
- carboxilo carboxilo amino carboxilo
- amino
- tiol carboxilo cloruro de acilo amino cloruro de acilo
- amino
- hidroxilo carboxilo anhídrido amino anhídrido
- tiol
- amino carboxilo éster amino éster
- tiol
- tiol
- carboxilo NHS amino NHS
- tiol
- hidroxilo carboxilo halógeno amino halógeno
- hidroxilo
- amino carboxilo éster sulfonato amino éster sulfonato
- hidroxilo
- tiol carboxilo maleimido amino maleimido
- hidroxilo
- hidroxilo
- carboxilo haloacetilo amino haloacetilo
- carboxilo
- isocianato amino isocianato
- cloruro de acilo
- carboxilo tiol carboxilo
- cloruro de acilo
- cloruro de acilo
- tiol
- cloruro de acilo
- cloruro de acilo
- anhídrido tiol anhídrido
- cloruro de acilo
- éster tiol éster
- cloruro de acilo
- NHS tiol NHS
- cloruro de acilo
- halógeno tiol halógeno
- cloruro de acilo
- éster sulfonato tiol éster sulfonato
- cloruro de acilo
- maleimido tiol maleimido
- cloruro de acilo
- haloacetilo tiol haloacetilo
- cloruro de acilo
- isocianato tiol isocianato
- anhídrido
- carboxilo hidroxilo carboxilo
- anhídrido
- cloruro de acilo hidroxilo cloruro de acilo
- anhídrido
- anhídrido
- hidroxilo
- anhídrido
- anhídrido
- éster hidroxilo éster
- anhídrido
- NHS hidroxilo NHS
- anhídrido
- halógeno hidroxilo halógeno
- anhídrido
- éster sulfonato hidroxilo éster sulfonato
- anhídrido
- maleimido hidroxilo maleimido
- anhídrido
- haloacetilo hidroxilo haloacetilo
- anhídrido
- isocianato hidroxilo isocianato
- éster
- carboxilo
- éster
- cloruro de acilo
- éster
- anhídrido
- éster
- éster
- éster
- NHS
- éster
- halógeno
- éster
- éster sulfonato
- éster
- maleimido
- éster
- haloacetilo
- éster
- isocianato
- NHS
- carboxilo
- NHS
- cloruro de acilo
- NHS
- anhídrido
- NHS
- éster
- NHS
- NHS
- NHS
- halógeno
- NHS
- éster sulfonato
- NHS
- maleimido
- NHS
- haloacetilo
- NHS
- isocianato
- halógeno
- carboxilo
- halógeno
- cloruro de acilo
- halógeno
- anhídrido
- halógeno
- éster
- halógeno
- NHS
- halógeno
- halógeno
- halógeno
- éster sulfonato
- halógeno
- maleimido
- halógeno
- haloacetilo
- halógeno
- isocianato
- éster sulfonato
- carboxilo
126
- éster sulfonato
- cloruro de acilo
- éster sulfonato
- anhídrido
- éster sulfonato
- éster
- éster sulfonato
- NHS
- éster sulfonato
- halógeno
- éster sulfonato
- éster sulfonato
- éster sulfonato
- maleimido
- éster sulfonato
- haloacetilo
- éster sulfonato
- isocianato
- maleimido
- carboxilo
- maleimido
- cloruro de acilo
- maleimido
- anhídrido
- maleimido
- éster
- maleimido
- NHS
- maleimido
- halógeno
- maleimido
- éster sulfonato
- maleimido
- maleimido
- maleimido
- haloacetilo
- maleimido
- isocianato
- haloacetilo
- carboxilo
- haloacetilo
- cloruro de acilo
- haloacetilo
- anhídrido
- haloacetilo
- éster
- haloacetilo
- NHS
- haloacetilo
- halógeno
- haloacetilo
- éster sulfonato
- haloacetilo
- maleimido
- haloacetilo
- haloacetilo
- haloacetilo
- isocianato
- isocianato
- carboxilo
- isocianato
- cloruro de acilo
- isocianato
- anhídrido
- isocianato
- éster
- isocianato
- NHS
- isocianato
- halógeno
- isocianato
- éster sulfonato
- isocianato
- maleimido
- isocianato
- haloacetilo
- isocianato
- isocianato
[0723] En algunas realizaciones, L es hidrófobo. Los enlazadores hidrófobos se conocen en la técnica. Véase, por ejemplo, Bioconjugate Techniques, GT Hermanson (Academic Press, San Diego, CA, 1996). Los grupos de unión hidrófobos adecuados conocidos en la técnica incluyen, por ejemplo, ácido 8-hidroxioctanoico ácido y 8
5 mercaptooctanoico. Antes de la conjugación con los péptidos de la composición, el grupo de unión hidrófobo comprende al menos dos grupos reactivos (A y B), como se describe en el presente documento y como se muestra a continuación:
10
[0724] En algunas realizaciones, el grupo de unión hidrófobo comprende ya sea un maleimido o un grupo yodoacetilo y, o bien un ácido carboxílico o un ácido carboxílico activado (por ejemplo, éster de NHS) como los grupos reactivos. En estas realizaciones, el grupo maleimido o yodoacetilo se puede acoplar a un resto tiol en Q o Y 20 y el ácido carboxílico o ácido carboxílico activado puede acoplarse a una amina en Q o Y con o sin el uso de un reactivo de acoplamiento. Cualquier agente de acoplamiento conocido por un experto en la técnica puede ser utilizado para acoplar el ácido carboxílico con la amina libre tal como, por ejemplo, DCC, DIC, HATU, HBTU, TBTU, y otros agentes de activación descrito en el presente documento. En realizaciones específicas, el grupo de unión hidrófilo comprende una cadena alifática de 2 a 100 grupos metileno en la que A y B son grupos o derivados de 25 carboxilo de los mismos (por ejemplo, ácido succínico). En otras realizaciones específicas el L es el ácido
127
Claims (1)
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imagen1 imagen2 imagen3 imagen4 imagen5 imagen6
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-
2012
- 2012-11-16 JP JP2014542489A patent/JP6324315B2/ja active Active
- 2012-11-16 CN CN201280049164.2A patent/CN103957927B/zh not_active Expired - Fee Related
- 2012-11-16 RU RU2014117678/04A patent/RU2014117678A/ru not_active Application Discontinuation
- 2012-11-16 WO PCT/US2012/065492 patent/WO2013074910A1/en not_active Ceased
- 2012-11-16 HK HK14112265.7A patent/HK1198810A1/xx unknown
- 2012-11-16 BR BR112014007124A patent/BR112014007124A2/pt unknown
- 2012-11-16 EP EP12849285.7A patent/EP2780031B1/en not_active Not-in-force
- 2012-11-16 KR KR20147012192A patent/KR20140097151A/ko not_active Withdrawn
- 2012-11-16 ES ES12849285.7T patent/ES2672880T3/es active Active
- 2012-11-16 MX MX2014003579A patent/MX2014003579A/es unknown
- 2012-11-16 US US13/679,121 patent/US8859491B2/en not_active Expired - Fee Related
- 2012-11-16 CA CA 2847246 patent/CA2847246A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| MX2014003579A (es) | 2015-04-10 |
| BR112014007124A2 (pt) | 2017-06-13 |
| CN103957927B (zh) | 2016-11-09 |
| EP2780031A1 (en) | 2014-09-24 |
| JP2015504431A (ja) | 2015-02-12 |
| JP6324315B2 (ja) | 2018-05-16 |
| EP2780031A4 (en) | 2015-08-05 |
| US20130157934A1 (en) | 2013-06-20 |
| WO2013074910A1 (en) | 2013-05-23 |
| RU2014117678A (ru) | 2015-12-27 |
| CA2847246A1 (en) | 2013-05-23 |
| HK1198810A1 (en) | 2015-06-12 |
| KR20140097151A (ko) | 2014-08-06 |
| EP2780031B1 (en) | 2018-03-07 |
| CN103957927A (zh) | 2014-07-30 |
| US8859491B2 (en) | 2014-10-14 |
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