ES2509883T3 - Antagonistas de glucagón - Google Patents

Antagonistas de glucagón Download PDF

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Publication number
ES2509883T3
ES2509883T3 ES08845852.6T ES08845852T ES2509883T3 ES 2509883 T3 ES2509883 T3 ES 2509883T3 ES 08845852 T ES08845852 T ES 08845852T ES 2509883 T3 ES2509883 T3 ES 2509883T3
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glucagon
kda peg
seq
pla6
antagonism
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Richard D. Dimarchi
Bin Yang
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Indiana University Research and Technology Corp
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Indiana University Research and Technology Corp
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Toxicology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Antagonista de glucagón que comprende la secuencia de la SEQ ID NO: 42, o un derivado de la SEQ ID NO: 42 que difiere de la SEQ ID NO: 42 por sustituciones de aminoácidos en una a tres posiciones de aminoácidos seleccionadas entre las posiciones 5, 6, 8, 9, 12, 13 y 14 de la SEQ ID NO: 42, en la que el NH2 N-terminal del antagonista de glucagón "o derivado" está sustituido por un grupo hidroxilo, de manera que la Phe en la posición 1 del antagonista de glucagón es ácido fenil láctico (PLA), y sales farmacéuticamente del mismo.

Description

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E08845852
02-10-2014
selectivamente sin la restauración del agonismo del glucagón. Los análogos Phe6 nativos sorprendentemente demuestran una restauración del agonismo cuando se pegilan. Sin embargo, esta restauración del agonismo no se observa en los análogos peptídicos PLA6. Se examinaron varios sitios de pegilación específicos, incluyendo las posiciones de aminoácido 8, 11 y 24 (en relación con el péptido de glucagón nativo). La pegilación en la posición 24 del análogo PLA6 muestra el antagonismo de glucagón más potente y selectivo.

Tabla 12: Análogos de glucagón truncados en N-terminal PEGilados y sus actividades de antagonismo del glucagón
Péptido
IC50 (nM) (unión al receptor) IC50 (nM) (cAMP, inhibición de glucagón 0,2 mM)
[C8 (20 kDa PEG), E9]Glucagón (aa6-29)-NH2
> 1000 sin antagonismo
[PLA6, C8 (20 kDa PEG), E9]Glucagón (aa6-29)-NH2
303 ± 14 236
[E9, C11 (20 kDa PEG)]Glucagón (aa6-29)-NH2
> 1000 sin antagonismo
[PLA6, E9, C11 (20 kDa PEG)]Glucagón (aa6-29)-NH2
776 ± 161 664
[E9, C24 (20 kDa PEG)]Glucagón (aa6-29)-NH2
> 1000 sin antagonismo
[PLA6, E9, C24 (20 kDa PEG)]Glucagón (aa6-29)-NH2
90 ± 7 126
[MCA6, E9, C24 (20 kDa PEG)]Glucagón (aa6-29)-NH2
208 ± 57 sin antagonismo
[C5 (1,2 kDa PEG), E9]Glucagón (aa5-29)-NH2
1081 ± 268 2281
[C5 (5 kDa PEG), E9]Glucagón (aa5-29)-NH2
634 ± 174 1608
[C5 (20 kDa PEG), E9]Glucagón (aa5-29)-NH2
331 ± 74 976
[d-Cys5 (20 kDa PEG), E9]Glucagón (aa5-29)-NH2
> 10000 14764
[K5(CH2CH2S-20 kDa PEG), E9]Glucagón (aa5-29)-NH2
> 10000 sin antagonismo
3,4 kDaPEG-dímero [C5, E9]Glucagón (aa5-29)-NH2
435 ± 256 1343
[PLA6, C8 (1,2 kDa PEG),E9] Glucagón (aa6-29)-NH2
220 ± 36 sin antagonismo
[PLA6, C8 (5 kDa PEG),E9] Glucagón (aa6-29)-NH2
948 ± 297 216
[PLA6, C8 (20 kDa PEG),E9] Glucagón (aa6-29)-NH2
303 ± 14 92
[PLA6, E9, C24 (1,2 kDa PEG)] Glucagón (aa6-29)-NH2
4,7 ± 0,4 18
[PLA6, E9, C24 (20 kDa PEG)] Glucagón (aa6-29)-NH2
90 ± 7 126
[MCA6, E9, C24 (20 kDa PEG)] Glucagón (aa6-29)-NH2
208 ± 57 sin antagonismo
[Phe6, E9, C24 (20 kDa PEG)] Glucagón (aa6-29)-NH2
> 10000 sin antagonismo
10 EJEMPLO 17
[0279] Los antagonistas de glucagón descritos en este documento se acilan de la siguiente manera: Los péptidos acilados y/o PEGilados se preparan de la siguiente manera. Los péptidos se sintetizan en una resina de soporte sólido utilizando un sintetizador de péptidos CS Bio 4886 o un sintetizador de péptidos Applied Biosystems
15 430A. Se utiliza química de neutralización in situ tal como se describe por Schnolzer et al., Int. J. Peptide Protein Res.
40: 180-193 (1992). Para los péptidos acilados, el residuo de aminoácido diana a acilar (por ejemplo, la posición diez) se sustituye por un resduo de N ε-Fmoc lisina. El tratamiento del péptido protegido N-terminalmente con BOC completado con piperidina al 20% en DMF durante 30 minutos elimina los grupos FMOC/formilo. El acoplamiento al residuo de Lys con el ε-amino libre se logra mediante el acoplamiento de un exceso molar de diez veces de un aminoácido espaciador
20 protegido con FMOC (por ejemplo, FMOC-(N-BOC)-triptófano-OH) o la cadena de acilo (por ejemplo, C17-COOH) y el reactivo de acoplamiento PyBOP o DEPBT en DMF/DIEA. La eliminación posterior del grupo Fmoc del aminoácido espaciador va seguida por la repetición del acoplamiento con una cadena de acilo. El tratamiento final con 100% de TFA da lugar a la eliminación de cualquier grupo protectore de la cadena lateral y el grupo BOC N-terminal. Las resinas de
49
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Claims (1)

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ES08845852.6T 2007-10-30 2008-10-23 Antagonistas de glucagón Active ES2509883T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US98378307P 2007-10-30 2007-10-30
US983783P 2007-10-30
PCT/US2008/080973 WO2009058662A2 (en) 2007-10-30 2008-10-23 Glucagon antagonists

Publications (1)

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ES2509883T3 true ES2509883T3 (es) 2014-10-20

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US (1) US8981047B2 (es)
EP (1) EP2217701B9 (es)
JP (1) JP5669582B2 (es)
AR (1) AR069110A1 (es)
AU (1) AU2008318986B2 (es)
CA (1) CA2707861A1 (es)
CL (1) CL2008003222A1 (es)
ES (1) ES2509883T3 (es)
HK (1) HK1143994A1 (es)
MX (1) MX2010004297A (es)
PE (1) PE20091393A1 (es)
TW (1) TW200920404A (es)
WO (1) WO2009058662A2 (es)

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