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ES2495741T3 - Compuestos de GLP-1 - Google Patents

Compuestos de GLP-1 Download PDF

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Publication number
ES2495741T3
ES2495741T3 ES07761068.1T ES07761068T ES2495741T3 ES 2495741 T3 ES2495741 T3 ES 2495741T3 ES 07761068 T ES07761068 T ES 07761068T ES 2495741 T3 ES2495741 T3 ES 2495741T3
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amide
lvkgr
lys
xaa
hgegt ftsdv
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Colin Victor Gegg, Jr.
Leslie Phillip MIRANDA
Katherine Ann WINTERS
Murielle Veniant-Ellison
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Amgen Inc
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Amgen Inc
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Abstract

Un compuesto de GLP-1 que comprende un análogo de GLP-1 que comprende la secuencia de aminoácidos de fórmula I (SEC ID Nº: 5): Xaa7-Gly-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Cys-Xaa24- Xaa25-Xaa26-Xaa27Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Gly-Xaa36-Xaa37-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser-C(O)-R1 en la que R1 es OR2 o NR2R3; R2 y R3 son independientemente hidrógeno o alquilo (C1-C8); Xaa en la posición 7 es: L-histidina, D-histidina, desamino-histidina, 2-amino-histidina, 3-hidroxi-histidina, homohistidina, β-fluorometil-histidina o β-metil-histidina; Xaa en la posición 9 es Glu, Asp o Lys; Xaa en la posición 10 es Gly o His; Xaa en la posición 11 es Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp o Lys; Xaa en la posición 12 es: His, Trp, Phe o Tyr; Xaa en la posición 13 es Thr o Gly; Xaa en la posición 14 es Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp o Lys; Xaa en la posición 15 es Asp o Glu; Xaa en la posición 16 es Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, Trp o Lys; Xaa en la posición 17 es Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp o Lys; Xaa en la posición 18 es Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, Trp, Tyr, Lys, homolisina, ornitina, 4-carboxifenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 19 es Tyr, Phe, Trp, Glu, Asp, Gln, Lys, homolisina, ornitina, 4-carboxi-fenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 20 es Leu, Ala, Gly, Ser, Thr, Ile, Val, Glu, Asp, Met, Trp, Tyr, Lys, homolisina, ornitina, 4- carboxi-fenilalanina, ácido beta-glutámico o ácido homoglutámico; Xaa en la posición 21 es Glu, Asp, Lys, homolisina, ornitina, 4-carboxi-fenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 22 es Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys, homolisina, ornitina, 4-carboxifenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 24 es Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, Lys, homolisina, ornitina, 4-carboxifenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 25 es Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys, homolisina, ornitina, 4-carboxifenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 26 es Lys, homolisina, Arg, Gln, Glu, Asp, His, ornitina, 4-carboxi-fenilalanina, ácido beta40 glutámico o ácido homoglutámico; Xaa en la posición 27 es Leu, Glu, Asp, Lys, homolisina, ornitina, 4-carboxi-fenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 28 es Phe, Trp, Asp, Glu, Lys, homolisina, ornitina, 4-carboxi-fenilalanina, ácido betaglutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 29 es Ile, Leu, Val, Ala, Phe, Asp, Glu, Lys, homolisina, ornitina, 4-carboxi-fenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 30 es Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys, homolisina, ornitina, 4-carboxifenilalanina, ácido beta-glutámico, ácido beta-homoglutámico o ácido homoglutámico; Xaa en la posición 31 es Trp, Phe, Tyr, Glu, Asp o Lys; Xaa en la posición 32 es Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp o Lys; Xaa33 es: Val o Lys; Xaa34 es: Lys o Asn; Xaa36 es: Arg o Gly; Xaa37 es: Gly o Pro; en la que el compuesto tiene una actividad de GLP-1, en la que dicha actividad de GLP-1 es actividad insulinotrópica.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
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imagen9
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imagen12
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imagen15
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imagen17
imagen18
imagen19
imagen20
E07761068
25-08-2014
Análogo de GLP-1
Ref. interna SEC ID Nº:
HGEGT FTSDV SSYLE GCAAK EFIAW LVKGR GSSGA PPPS
cgGLP-12, 14 7
HGEGT FTSDV SSYLE GCAAK EFIAW LKNGG PSSGA PPPS
cgGLP-13, 15 8
XXXXX XXXXX XXXXX XXXXX XXXXX XXXXX XCSGG
Fórmula II 9
HGEGT FTSDV SSYLE GQAAK EFIAW LVKGR GCSG
cgGLP-4-6, 8, 10, 16 10
HZEGT FTSDV SSYLE GQAAK EFIAW LVKGR GCSGG
cgGLP-17 11
H[bAla]EGT FTSDV SSYLE GQAAK EFIAW LVKGR GCSGG
cgGLP-18 12
XXXXX XXXXX XXXXX XXXXX XXXXX XXXXX GXXXX
Fórmula III 13
HAEGT FTSDV SSYLE ZQAAK EFIAW LVKGR-amida
14
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR G-amida
15
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GC
16
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GC-amida
cgGLP-23 17
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCA-amida
cgGLP30 y mgGLP 20 18
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCG
19
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCG-amida
mgGLP-16 20
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCSG
cgGLP-19 21
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCSG-amida
cgGLP-24-29, mgGLP22, mgGLP-33, mgGLP-27 22
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCSGG
23
HGEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCSGG-amida
mgGLP-15 24
HZEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCSG
cgGLP-20 25
HZEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GCSGG
26
HZEGT FTSDV SSYLE ZQAAK EFIAW LVKGR GGC
cgGLP-22 27
HGEGT FTSDV SSYLE [Aad]QAAK EFIAW LVKGR GCSG
cgGLP-21 28
Fórmula IV
29
HGEGT FTSDV SSYLE EQAAKEFIAW LVKGR G-amida
cicloE22-R26 (mgGLP-24) 30
HGEGT FTSDV SSYLE EQAAKEFIAW LVKGR GCA-amida
31
HGEGT FTSDV SSYLE EQAAKEFIAW LVKGR GCSG-amida
cicloE22-K26/CSG 32
HGEGT FTSDV SEYLE KQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn 38 33
HGEGT FTSDV SSELE GKAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [19-23] -Lys/Orn 38 34
HGEGT FTSDV SSYEE GQKAK EFIAW LVKGR G[K/O/C]-amida
[GlyB]GLP1(7-37) ciclo[Glu14-Lys18]38 35
HGEGT FTSDV SSYLE GQAKK EFIAW LVKGR G[K/O/C]-amida
[Gly8]GLP1(7-37) cyc[Glu15-Lys19] 36
HGEGT FTSDV SSYLE EQAAKEFIAW LVKGR G[K/O/C]-amida
G8 ciclo[22-26] -Lys/Orn 38 37
HGEGT FTSDV SSYLE GEAAKKFIAW LVKGR G[K/O/C]-amida
[Gly8]GLP1(7-37) ciclo[Glu17-Lys21] 38
HGEGT FTSDV SSYLE GQEAK EKIAW LVKGR G[K/O/C]-amida
[Gly8]GLP1(7-37) ciclo[Glu18-Lys22] 39
HGEGT FTSDV SSYLE GQAEK EFKAW LVKGR G[K/O/C]-amida
G8 ciclo [25-29] -Lys/Orn 38 40
HGEGT FTSDV SSYLE GQAAEEFIKW LVKGR G[K/O/C)-amida
G8 ciclo [26-30] -Lys/Orn 38 41
HGEGT FTSDV SSYLE GQAAKEFIAW LVKGR G[K/O/C]-amida
[Gly8]ciclo[21-26] GLP1(737)-amida 42
HGEGT FTSDV SSYLE JQAAKEFIAW LVKGR G-amida
cicloJ22-K26 43
HGEGT FTSDV SSYLE JQAAKEFIAW LVKGR GCA-amida
cicloJ22-K26 44
HGEGT FTSDV SSYLE JQAAKEFIAW LVKGR GCSG-amida
cicloJ22-K26/CSG 45
HGEGT FTSDV SJYLE KQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn/Cys 38 46
HGEGT FTSDV SSJLE GKAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [19-23] -Lys/Orn/Cys 38 47
HGEGT FTSDV SSYJE GQKAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [20-24] -Lys/Orn/Cys 38 48
HGEGT FTSDV SSYLJ GQAKK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-25] -Lys/Orn/Cys 38 49
HGEGT FTSDV SSYLE JQAAKEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [22-26] -Lys/Orn/Cys 38 50
22
E07761068
25-08-2014
Análogo de GLP-1
Ref. interna SEC ID Nº:
HGEGT FTSDV SSYLE GJAAKKFIAW LVKGR G[K/O/C]-amida
G8 ciclo [23-27] -Lys/Orn/Cys 38 51
HGEGT FTSDV SSYLE GQJAK EKIAW LVKGR G[K/O/C]-amida
G8 ciclo [24-28] -Lys/Orn/Cys 38 52
HGEGT FTSDV SSYLE GQAJK EFKAW LVKGR G[K/O/C]-amida
G8 ciclo [25-29] -Lys/Orn/Cys 38 53
HGEGT FTSDV SSYLE GQAAJEFIKW LVKGR G[K/O/C]-amida
G8 ciclo [26-30] -Lys/Orn/Cys 38 54
HGEGT FTSDV SSYLJ GQAAKEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-26] -Lys/Orn/Cys 38 55
HGEGT FTSDV SSYLE KQAAJEFIAW LVKGR G-amida
56
HGEGT FTSDV SSYLE KQAAJEFIAW LVKGR GCA-amida
57
HGEGT FTSDV SSYLE KQAAJEFIAW LVKGR GCSG-amida
58
HGEGT FTSDV SKYLE JQAAK EFIAW LVKGR G[K/O/C]-amida
59
HGEGT FTSDV SSKLE GJAAK EFIAW LVKGR G[K/O/C]-amida
60
HGEGT FTSDV SSYKE GQJAK EFIAW LVKGR G[K/O/C]-amida
61
HGEGT FTSDV SSYLK GQAJK EFIAW LVKGR G[K/O/C]-amida
62
HGEGT FTSDV SSYLE KQAAJEFIAW LVKGR G[K/O/C]-amida
63
HGEGT FTSDV SSYLE GKAAKJFIAW LVKGR G[K/O/C]-amida
64
HGEGT FTSDV SSYLE GQKAK EJIAW LVKGR G[K/O/C]-amida
65
HGEGT FTSDV SSYLE GQAKK EFJAW LVKGR G[K/O/C]-amida
66
HGEGT FTSDV SSYLE GQAAKEFIJW LVKGR G[K/O/C]-amida
67
HGEGT FTSDV SSYLK GQAAJEFIAW LVKGR G[K/O/C]-amida
68
HGEGT FTSDV SSYLE EQAAOEFIAW LVKGR G-amida
cicloE22-026 69
HGEGT FTSDV SSYLE EQAAOEFIAW LVKGR GCA-amida
cicloE22-026 70
HGEGT FTSDV SSYLE EQAAOEFIAW LVKGR GCSG-amida
cicloE22-026/CSG 71
HGEGT FTSDV SEYLE OQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn/Cys 38 72
HGEGT FTSDV SSELE GOAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [19-23] -Lys/Orn/Cys 38 73
HGEGT FTSDV SSYEE GQOAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [20-24] -Lys/Orn/Cys 38 74
HGEGT FTSDV SSYLE GQAOK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-25] -Lys/Orn/Cys 38 75
HGEGT FTSDV SSYLE EQAAOEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [22-26] -Lys/Orn/Cys 38 76
HGEGT FTSDV SSYLE GEAAKOFIAW LVKGR G[K/O/C]-amida
G8 ciclo [23-27] -Lys/Orn/Cys 38 77
HGEGT FTSDV SSYLE GQEAK EOIAW LVKGR G[K/O/C]-amida
G8 ciclo [24-28] -Lys/Orn/Cys 38 78
HGEGT FTSDV SSYLE GQAEK EFOAW LVKGR G[K/O/C]-amida
G8 ciclo [25-29] -Lys/Orn/Cys 38 79
HGEGT FTSDV SSYLE GQAAEEFIOW LVKGR G[K/O/C]-amida
G8 ciclo [26-30] -Lys/Orn/Cys 38 80
HGEGT FTSDV SSYLE GQAAOEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-26] -Lys/Orn/Cys 38 81
HGEGT FTSDV SSYLE OQAAEEFIAW LVKGR G-amida
82
HGEGT FTSDV SSYLE OQAAEEFIAW LVKGR GCA-amida
83
HGEGT FTSDV SSYLE OQAAEEFIAW LVKGR GCSG-amida
84
HGEGT FTSDV SOYLE EQAAK EFIAW LVKGR G[K/O/C]-amida
85
HGEGT FTSDV SSOLE GEAAK EFIAW LVKGR G[K/O/C]-amida
86
HGEGT FTSDV SSYOE GQEAK EFIAW LVKGR G[K/O/C]-amida
87
HGEGT FTSDV SSYLO GQAEK EFIAW LVKGR G[K/O/C]-amida
88
HGEGT FTSDV SSYLE OQAAEEFIAW LVKGR G[K/O/C]-amida
89
HGEGT FTSDV SSYLE GOAAKEFIAW LVKGR G[K/O/C]-amida
90
HGEGT FTSDV SSYLE GQOAK EEIAW LVKGR G[K/O/C]-amida
91
HGEGT FTSDV SSYLE GQAOK EFEAW LVKGR G[K/O/C]-amida
92
HGEGT FTSDV SSYLE GQAAOEFIEW LVKGR G[K/O/C]-amida
93
HGEGT FTSDV SSYLO GQAAEEFIAW LVKGR G[K/O/C]-amida
94
HGEGT FTSDV SSYLE DQAAOEFIAW LVKGR G-amida
cicloD22-K26 95
HGEGT FTSDV SSYLE DQAAOEFIAW LVKGR GCA-amida
cicloD22-K26 96
23
E07761068
25-08-2014
Análogo de GLP-1
Ref. interna SEC ID Nº:
HGEGT FTSDV SSYLE DQAAOEFIAW LVKGR GCSG-amida
cicloD22-K26/CSG 97
HGEGT FTSDV SDYLE OQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn/Cys 38 98
HGEGT FTSDV SSDLE GOAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [19-23] -Lys/Orn/Cys 38 99
HGEGT FTSDV SSYDE GQOAK EFIAW LVKGR G[K/O/C]-amida
GB ciclo [20-24] -Lys/Orn/Cys 38 100
HGEGT FTSDV SSYLD GQAOK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-25] -Lys/Orn/Cys 38 101
HGEGT FTSDV SSYLE DQAAOEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [22-26] -Lys/Orn/Cys 38 102
HGEGT FTSDV SSYLE GDAAKOFIAW LVKGR G[K/O/C]-amida
G8 ciclo [23-27] -Lys/Orn/Cys 38 103
HGEGT FTSDV SSYLE GQDAK EOIAW LVKGR G[K/O/C]-amida
G8 ciclo [24-28] -Lys/Orn/Cys 38 104
HGEGT FTSDV SSYLE GQADK EFOAW LVKGR G[K/O/C]-amida
G8 ciclo [25-29] -Lys/Orn/Cys 38 105
HGEGT FTSDV SSYLE GQAADEFIOW LVKGR G[K/O/C]-amida
G8 ciclo [26-30] -Lys/Orn/Cys 38 106
HGEGT FTSDV SSYLE OQAADEFIAW LVKGR G-amida
107
HGEGT FTSDV SSYLE OQAADEFIAW LVKGR GCA-amida
108
HGEGT FTSDV SSYLE OQAADEFIAW LVKGR GCSG-amida
109
HGEGT FTSDV SOYLE DQAAK EFIAW LVKGR G[K/O/C]-amida
110
HGEGT FTSDV SSOLE GDAAK EFIAW LVKGR G[K/O/C]-amida
111
HGEGT FTSDV SSYOE GQDAK EFIAW LVKGR G[K/O/C]-amida
112
HGEGT FTSDV SSYLO GQADK EFIAW LVKGR G[K/O/C]-amida
113
HGEGT FTSDV SSYLE OQAADEFIAW LVKGR G[K/O/C]-amida
114
HGEGT FTSDV SSYLE GOAAKDFIAW LVKGR G[K/O/C]-amida
115
HGEGT FTSDV SSYLE GQOAK EDIAW LVKGR G[K/O/C]-amida
116
HGEGT FTSDV SSYLE GQAOK EFDAW LVKGR G[K/O/C]-amida
117
HGEGT FTSDV SSYLE GQAAOEFIDW LVKGR G[K/O/C]-amida
118
HGEGT FTSDV SSYLE GQAAOEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-26] -Lys/Orn/Cys 38 119
HGEGT FTSDV SSYLO GQAAEEFIAW LVKGR G[K/O/C]-amida
120
HGEGT FTSDV SSYLE GQAAKEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-26] -Lys/Orn/Cys 38 121
HGEGT FTSDV SSYLK GQAAEEFIAW LVKGR G[K/O/C]-amida
122
HGEGT FTSDV SSYLJ GQAAKEFIAW LVKGR G[K/O/C]-amida
123
HGEGT FTSDV SSYLK GQAAJEFIAW LVKGR G[K/O/C]-amida
124
HGEGT FTSDV SSYLD GQAAOEFIAW LVKGR G[K/O/C]-amida
125
HGEGT FTSDV SSYLO GQAADEFIAW LVKGR G[K/O/C]-amida
126
HGEGT FTSDV SSYLD GQAAKEFIAW LVKGR G[K/O/C]-amida
127
HGEGT FTSDV SSYLK GQAADEFIAW LVKGR G[K/O/C]-amida
128
HGEGT FTSDV SSYL [Cpa] GQAAO EFIAW LVKGR G[K/O/C]-amida
129
HGEGT FTSDV SSYLO GQAA [Cpa] EFIAW LVKGR G[K/O/C]-amida
130
HGEGT FTSDV SSYL [Cpa]GQAAK EFIAW LVKGR G[K/O/C]-amida
131
HGEGT FTSDV SSYLK GQAA[Cpa] EFIAW LVKGR G[K/O/C]-amida
132
HGEGT FTSDV SSYLB GQAAKEFIAW LVKGR G[K/O/C]-amida
133
HGEGT FTSDV SSYLK GQAABEFIAW LVKGR G[K/O/C]-amida
134
HGEGT FTSDV SSYLE DQAAKEFIAW LVKGR G-amida
cicloD22-K26 135
HGEGT FTSDV SSYLE DQAAKEFIAW LVKGR GCA-amida
cicloD22-K26 136
HGEGT FTSDV SSYLE DQAAKEFIAW LVKGR GCSG-amida
cicloD22-K26/CSG 137
HGEGT FTSDV SDYLE KQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn/Cys 38 138
HGEGT FTSDV SSDLE GKAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [19-23] -Lys/Orn/Cys 38 139
HGEGT FTSDV SSYDE GQKAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [20-24] -Lys/Orn/Cys 38 140
HGEGT FTSDV SSYLD GQAKK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-25] -Lys/Orn/Cys 38 141
HGEGT FTSDV SSYLE DQAAKEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [22-26] 142
24
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Ref. interna SEC ID Nº:
-Lys/Orn/Cys 38
HGEGT FTSDV SSYLE GDAAKKFIAW LVKGR G[K/O/C]-amida
G8 ciclo [23-27] -Lys/Orn/Cys 38 143
HGEGT FTSDV SSYLE GQDAK EKIAW LVKGR G[K/O/C]-amida
G8 ciclo [24-28] -Lys/Orn/Cys 38 144
HGEGT FTSDV SSYLE GQADK EFKAW LVKGR G[K/O/C]-amida
G8 ciclo [25-29] -Lys/Orn/Cys 38 145
HGEGT FTSDV SSYLE GQAADEFIKW LVKGR G[K/O/C]-amida
G8 ciclo [26-30] -Lys/Orn/Cys 38 146
HGEGT FTSDV SSYLE KQAADEFIAW LVKGR G-amida
147
HGEGT FTSDV SSYLE KQAADEFIAW LVKGR GCA-amida
148
HGEGT FTSDV SSYLE KQAADEFIAW LVKGR GCSG-amida
149
HGEGT FTSDV SKYLE DQAAK EFIAW LVKGR G[K/O/C]-amida
150
HGEGT FTSDV SSKLE GDAAK EFIAW LVKGR G[K/O/C]-amida
151
HGEGT FTSDV SSYKE GQDAK EFIAW LVKGR G[K/O/C]-amida
152
HGEGT FTSDV SSYLK GQADK EFIAW LVKGR G[K/O/C]-amida
153
HGEGT FTSDV SSYLE KQAADEFIAW LVKGR G[K/O/C]-amida
154
HGEGT FTSDV SSYLE GKAAKDFIAW LVKGR G[K/O/C]-amida
155
HGEGT FTSDV SSYLE GQKAK EDIAW LVKGR G[K/O/C]-amida
156
HGEGT FTSDV SSYLE GQAKK EFDAW LVKGR G[K/O/C]-amida
157
HGEGT FTSDV SSYLE GQAKKEFIDW LVKGR G[K/O/C]-amida
158
HGEGT FTSDV SSYLE KQAAEEFIAW LVKGR G-amida
GLP1 (7-37) ciclo [Lys16-Glu20] 159
HGEGT FTSDV SSYLE KQAAEEFIAW LVKGR GCA-amida
cicloK22-E26 160
HGEGT FTSDV SSYLE KQAAEEFIAW LVKGR GCSG-amida
cicloK22-E26/CSG 161
HGEGT FTSDV SKYLE EQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn/Cys 38 162
HGEGT FTSDV SSKLE GEAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [19-23] -Lys/Orn/Cys 38 163
HGEGT FTSDV SSYKE GQEAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [20-24] -Lys/Orn/Cys 38 164
HGEGT FTSDV SSYLK GQAEK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [21-25] -Lys/Orn/Cys 38 165
HGEGT FTSDV SSYLE KQAAEEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [22-26] -Lys/Orn/Cys 38 166
HGEGT FTSDV SSYLE GKAAKEFIAW LVKGR G[K/O/C]-amida
G8 ciclo [23-27] -Lys/Orn/Cys 38 167
HGEGT FTSDV SSYLE GQKAK EEIAW LVKGR G[K/O/C]-amida
GB ciclo [24-28] -Lys/Orn/Cys 38 168
HGEGT FTSDV SSYLE GQAKK EFEAW LVKGR G[K/O/C]-amida
G8 ciclo [25-29] -Lys/Orn/Cys 38 169
HGEGT FTSDV SSYLE GQAAKEFIEW LVKGR G[K/O/C]-amida
G8 ciclo [26-30] -Lys/Orn/Cys 38 170
HGEGT FTSDV SS[Cpa]LE GQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo[19-26] -Lys/Orn/Cys 38 171
HGEGT FTSDV SSKLE GQAA[Cpa] EFIAW LVKGR G[K/O/C]-amida
172
HGEGT FTSDV SS[Cpa]LE GQAAO EFIAW LVKGR G[K/O/C]-amida
G8 ciclo[19-26] -Lys/Orn/Cys 38 173
HGEGT FTSDV SSOLE GQAA[Cpa] EFIAW LVKGR G[K/O/C]-amida
174
HGEGT FTSDL SSYLE BQAAKEFIAW LVKGR G-amida
175
HGEGT FTSDV SSYLE BQAAKEFIAW LVKGR GCA-amida
176
HGEGT FTSDV SSYLE BQAAKEFIAW LVKGR GCSG-amida
177
HGEGT FTSDV SBYLE KQAAK EFIAW LVKGR G[K/O/C]-amida
G8 ciclo [18-22] -Lys/Orn/Cys 38 178
HGEGT FTSDV SSBLE GKAAK EFIAW LVKGR G[K/O/C]-amida
179
HGEGT FTSDV SSYBE GQKAK EFIAW LVKGR G[K/O/C]-amida
180
HGEGT FTSDV SSYLB GQAKK EFIAW LVKGR G[K/O/C]-amida
181
HGEGT FTSDV SSYLE BQAAKEFIAW LVKGR G[K/O/C]-amida
182
HGEGT FTSDV SSYLE GBAAKKFIAW LVKGR G[K/O/C]-amida
183
HGEGT FTSDV SSYLE GQBAK EKIAW LVKGR G[K/O/C]-amida
184
HGEGT FTSDV SSYLE GQABK EFKAW LVKGR G[K/O/C]-amida
185
25
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Ref. interna SEC ID Nº:
HGEGT FTSDV SSYLE GQAABEFIKW LVKGR G[K/O/C]-amida
186
HGEGT FTSDV SKYLE BQAAK EFIAW LVKGR G[K/O/C]-amida
187
HGEGT FTSDV SSYLE KQAABEFIAW LVKGR G-amida
188
HGEGT FTSDV SSYLE KQAABEFIAW LVKGR GCA-amida
189
HGEGT FTSDV SSYLE KQAABEFIAW LVKGR GCSG-amida
190
HGEGT FTSDV SSKLE GBAAK EFIAW LVKGR G[K/O/C]-amida
191
HGEGT FTSDV SSYKE GQBAK EFIAW LVKGR G[K/O/C]-amida
192
HGEGT FTSDV SSYLK GQABK EFIAW LVKGR G[K/O/C]-amida
193
HGEGT FTSDV SSYLE KQAABEFIAW LVKGR G[K/O/C]-amida
194
HGEGT FTSDV SSYLE GKAAKBFIAW LVKGR G[K/O/C]-amida
195
HGEGT FTSDV SSYLE GQKAK EBIAW LVKGR G[K/O/C]-amida
196
HGEGT FTSDV SSYLE GQAKK EFBAW LVKGR G[K/O/C]-amida
197
HGEGT FTSDV SSYLE GQAAKEFIBW LVKGR G[K/O/C]-amida
198
HGEGT FTSDV SSYLE[Cpa]QAAK EFIAW LVKGR G-amida
199
HGEGT FTSDV SSYLE[Cpa]QAAK EFIAW LVKGR GCA-amida
200
HGEGT FTSDV SSYLE [Cpa]QAAK EFIAW LVKGR GCSG-amida
201
HGEGT FTSDV S[Cpa]YLEKQAAK EFIAW LVKGR G[K/O/C]-amida
202
HGEGT FTSDV SS[Cpa]LE GKAAK EFIAW LVKGR G[K/O/C]-amida
203
HGEGT FTSDV SSY[Cpa]E GQKAK EFIAW LVKGR G[K/O/C]-amida
204
HGEGT FTSDV SSYL[Cpa]GQAKK EFIAW LVKGR G[K/O/C]-amida
205
HGEGT FTSDV SSYLE[Cpa]QAAK EFIAW LVKGR G[K/O/C]-amida
206
HGEGT FTSDV SSYLE G[Cpa]AAK KFIAW LVKGR G[K/O/C]-amida
207
HGEGT FTSDV SSYLE GQ[Cpa]AK EKIAW LVKGR G[K/O/C]-amida
208
HGEGT FTSDV SSYLE GQA[Cpa]K EFKAW LVKGR G[K/O/C]-amida
209
HGEGT FTSDV SSYLE GQAA[Cpa] EFIKW LVKGR G[K/O/C]-amida
210
HGEGT FTSDV SKYLE[Cpa]QAAK EFIAW LVKGR G[K/O/C]-amida
211
HGEGT FTSDV SSYLEKQAA[Cpa] EFIAW LVKGR G-amida
212
HGEGT FTSDV SSYLEKQAA[Cpa] EFIAW LVKGR GCA-amida
213
HGEGT FTSDV SSYLEKQAA[Cpa] EFIAW LVKGR GCSG-amida
214
HGEGT FTSDV SSKLE G[Cpa]AAK EFIAW LVKGR G[K/O/C]-amida
215
HGEGT FTSDV SSYKE GQ[Cpa]AK EFIAW LVKGR G[K/O/C]-amida
216
HGEGT FTSDV SSYLKGQA[Cpa]K EFIAW LVKGR G[K/O/C]-amida
217
HGEGT FTSDV SSYLEKQAA[Cpa] EFIAW LVKGR G[K/O/C]-amida
218
HGEGT FTSDV SSYLE GKAAK[Cpa]FIAW LVKGR G[K/O/C]-amida
219
HGEGT FTSDV SSYLE GQKAK E[Cpa]IAW LVKGR G[K/O/C]-amida
220
HGEGT FTSDV SSYLE GQAKK EF[Cpa]AW LVKGR G[K/O/C]-amida
221
HGEGT FTSDV SSYLE GQAAKEFI[Cpa]W LVKGR G[K/O/C]-amida
222
HGEGT FTSDV SSYLE[Cpa]QAAO EFIAW LVKGR G-amida
223
HGEGT FTSDV SSYLE[Cpa]QAAO EFIAW LVKGR GCA-amida
224
HGEGT FTSDV SSYLE[Cpa]QAAO EFIAW LVKGR GCSG-amida
225
HGEGT FTSDV S[Cpa]YLEOQAAK EFIAW LVKGR G[K/O/C]-amida
226
HGEGT FTSDV SS[Cpa]LE GOAAK EFIAW LVKGR G[K/O/C]-amida
227
HGEGT FTSDV SSY[Cpa]E GQOAK EFIAW LVKGR G[K/O/C]-amida
228
HGEGT FTSDV SSYL[Cpa]GQAOK EFIAW LVKGR G[K/O/C]-amida
229
HGEGT FTSDV SSYLE[Cpa]QAAO EFIAW LVKGR G[K/O/C]-amida
230
HGEGT FTSDV SSYLE G[Cpa]AAK OFIAW LVKGR G[K/O/C]-amida
231
HGEGT FTSDV SSYLE GQ[Cpa]AK EOIAW LVKGR G[K/O/C]-amida
232
HGEGT FTSDV SSYLE GQA[Cpa]K EFOAW LVKGR G[K/O/C]-amida
233
HGEGT FTSDV SSYLE GQAA[Cpa] EFIOW LVKGR G[K/O/C]-amida
234
HGEGT FTSDV SOYLE[Cpa]QAAK EFIAW LVKGR G[K/O/C]-amida
235
HGEGT FTSDV SSYLEOQAA[Cpa] EFIAW LVKGR G-amida
236
HGEGT FTSDV SSYLEOQAA[Cpa] EFIAW LVKGR GCA-amida
237
HGEGT FTSDV SSYLEOQAA[Cpa] EFIAW LVKGR GCSG-amida
238
HGEGT FTSDV SSOLE G[Cpa]AAK EFIAW LVKGR G[K/O/C]-amida
239
HGEGT FTSDV SSYOE GQ[Cpa]AK EFIAW LVKGR G[K/O/C]-amida
240
HGEGT FTSDV SSYLOGQA[Cpa]K EFIAW LVKGR G[K/O/C]-amida
241
HGEGT FTSDV SSYLEOQAA[Cpa] EFIAW LVKGR G[K/O/C]-amida
242
HGEGT FTSDV SSYLE GOAAK[Cpa]FIAW LVKGR G[K/O/C]-amida
243
HGEGT FTSDV SSYLE GQOAK E[Cpa]IAW LVKGR G[K/O/C]-amida
244
HGEGT FTSDV SSYLE GQAOK EF[Cpa]AW LVKGR G[K/O/C]-amida
245
HGEGT FTSDV SSYLE GQAAOEFI[Cpa]W LVKGR G[K/O/C]-amida
246
26
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Ref. interna SEC ID Nº:
A HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
A-GLP-1 247
G HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
G-GLP-1 248
P HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
P-GLP-1 249
S HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
S-GLP-1 250
T HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
T-GLP-1 251
V HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
V-GLP-1 252
MQ HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MQ-GLP1 253
MR HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MR-GLP1 254
MK HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MK-GLP1 255
M HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
M-GLP1 256
MH HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MH-GLP1 257
MHH HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MHH-GLP1 258
MY HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MY-GLP1 259
MI HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MI-GLP1 260
MD HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MD-GLP1 261
ML HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
ML-GLP1 262
MN HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MN-GLP1 263
ME HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
ME-GLP1 264
MW HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MW-GLP1 265
MF HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MF-GLP1 266
MM HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
MM-GLP1 267
HGEGT FTSDV SSYLE GQAAK EFIAW LVKGR GCA-amida
268
HGEGT FTSDV SSYLE GQAAK EFIAW LVKGG G
269
HGEGT FTSDV SSYLE GQAAK EFIAW LKNGG G
270
HGEGT FTSDL SKQME EEAVR LFIEW LKNGG-amida
271
HGEGT FTSDL SKQME ZEAVR LFIEW LKNGG-amida
272
HGEGT FTSDV SSYLE GQAAK EFIAW L
273
HGEGT FTSDV SSYLE EQAKK EFIAW LVKGR G-amida
274
HGEGT FTSDV SSYLE EQAKK EFIAW LVKGR GCGS-amida
275
HGEGT FTSDV SSYLE GQAKK EFIAW LEKGR K-amida
277
HGEGT FTSDV SSYLEEQAADab EFIAW LVKGR G-amida
279
HGEGT FTSDV SSYLEEQAADab EFIAW LVKGR GCA-amida
280
HGEGT FTSDV SSYLEEQAADab EFIAW LVKGR GCSG-amida
281
HGEGT FTSDV SEYLEDabQAAK EFIAW LVKGR G[K/O/C]-amida
282
HGEGT FTSDV SSELE GDabAAK EFIAW LVKGR G[K/O/C]-amida
283
HGEGT FTSDV SSYEE GQDabAK EFIAW LVKGR G[K/O/C]-amida
284
HGEGT FTSDV SSYLEGQADabK EFIAW LVKGR G[K/O/C]-amida
285
HGEGT FTSDV SSYLEEQAADab EFIAW LVKGR G[K/O/C]-amida
286
HGEGT FTSDV SSYLE GEAAKDabFIAW LVKGR G[K/O/C]-amida
287
HGEGT FTSDV SSYLE GQEAK EDabIAW LVKGR G[K/O/C]-amida
288
HGEGT FTSDV SSYLE GQAEK EFDabAW LVKGR G[K/O/C]-amida
289
HGEGT FTSDV SSYLE GQAAEEFIDabW LVKGR G[K/O/C]-amida
290
HGEGT FTSDV SSYLEGQAADab EFIAW LVKGR G[K/O/C]-amida
291
HGEGT FTSDV SSYLEDabQAAE EFIAW LVKGR G-amida
292
HGEGT FTSDV SSYLEDabQAAE EFIAW LVKGR GCA-amida
293
HGEGT FTSDV SSYLEDabQAAE EFIAW LVKGR GCSG-amida
294
HGEGT FTSDV SDabYLEEQAAK EFIAW LVKGR G[K/O/C]-amida
295
HGEGT FTSDV SSDabLE GEAAK EFIAW LVKGR G[K/O/C]-amida
296
HGEGT FTSDV SSYDabE GQEAK EFIAW LVKGR G[K/O/C]-amida
297
HGEGT FTSDV SSYLDabGQAEK EFIAW LVKGR G[K/O/C]-amida
298
HGEGT FTSDV SSYLEDabQAAE EFIAW LVKGR G[K/O/C]-amida
299
HGEGT FTSDV SSYLE GDabAAK EFIAW LVKGR G[K/O/C]-amida
300
HGEGT FTSDV SSYLE GQDabAK EEIAW LVKGR G[K/O/C]-amida
301
HGEGT FTSDV SSYLE GQADabK EFEAW LVKGR G[K/O/C]-amida
302
HGEGT FTSDV SSYLE GQAADab EFIEW LVKGR G[K/O/C]-amida
303
HGEGT FTSDV SSYLDabGQAAE EFIAW LVKGR G[K/O/C]-amida
304
El término “análogo de GLP-1” también incluye variantes, fragmentos y derivados de los análogos de GLP-1 anteriores que son equivalentes funcionales a uno de los análogos de GLP-1 anteriores en los que la variante, fragmento o derivado tiene una secuencia de aminoácidos similar (por ejemplo, que comprende sustituciones 5 conservativas) y retiene, a cierto grado, al menos una actividad del análogo de GLP-1.
27
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
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cgGLP-6
SEC ID Nº: 10 + mancuerna de PEG de 8k 11 nM -0,1 nM 0,8 nM
cgGLP-8
SEC ID Nº: 10 + PEG de 30k 170 nM 0,4 nM 3 nM
cgGLP-10
SEC ID Nº: 10 + dímero de PEG de 20k 100 nM 0,6 nM 4 nM
cgGLP-16
SEC ID Nº: 10 + PEG de 30k 1 uM 0,39 nM 4 nM
H[Aib]EGT FTSDV SSYLE GQAAK EFIAW LVKGR GCSGG (SEC ID Nº: 11)
100 nM 4 nM >50 nM
cgGLP-17
SEC ID Nº: 11 + PEG de 20k 1 uM 20 nM >100 nM
H[bAla]EGT FTSDV SSYLE GQAAK EFIAW LVKGR GCSGG (SEC ID Nº: 12)
400 nM >100 nM indeterminada
cgGLP-18
SEC ID Nº: 12 + PEG de 20k >1 uM indeterminada indeterminada
Aib = ácido alfaaminobutírico bAla = ácido betaaminopropiónico
Ejemplo 6
Resultados con compuestos relacionados con la fórmula III
5 Se realizaron experimentos in vitro para determinar la potencia y unión del receptor para compuestos de GLP-1 que tienen tanto una sustitución de Aib (ácido 2-aminoisobutírico) como Aad (ácido 2-aminoadípico) en la posición 22 y sustitución opcional en la posición 8 y en el extremo C. Las moléculas pegiladas se conjugaron en la cisteína en la posición 38. Se realizaron experimentos como se describe en el Ejemplo 2, y los resultados se resumen en la Tabla
10 5 a continuación.
Tabla 5
REF INTERNA Nº
SECUENCIA CI50 humana CE50 humana CE50 deratón
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR -AMIDA (SEC ID Nº: 14)
2,5 nM 16 pM 0,15 nM
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR G-AMIDA (SEC ID Nº: 15)
3,5 nM 27 pM 0,12 nM
cgGLP-23
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GC-AMIDA SEC ID Nº: 17 + PEG de 20k 300 nM 0,2 nM 3 nM
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GCA-AMIDA (SEC ID Nº: 18)
25 pM 0,2 nM
mgGLP32 y mgGLP-20
SEC ID Nº: 18 + PEG de 20k 56 nM 0,13 nM 0,84 nM
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GCG-AMIDA (SEC ID Nº: 20)
mgGLP-16
SEC ID Nº: 20 + PEG de 20k 50 nM 0,2 nM 1,6 nM
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GCSG (SEC ID Nº: 21)
18 nM 68 pM 300 pM
mgGLP19 y cgGLP-19
SEC ID Nº: 21 + PEG de 20k 230 nM 0,32 nM 4 nM
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GCSG-AMIDA (SEC ID Nº: 22)
17 nM 45 pM 0,27 nM
cgGLP-24 cgGLP-27, mgGLP-22, mgGLP-33 y mgGLP-27
SEC ID Nº: 22 + PEG de 20k 47 nM 0,1 nM 0,84 nM
cgGLP-25
SEC ID Nº: 22 + 5k PEG 15 nM 39 pM 0,9 nM
cgGLP-26
SEC ID Nº: 22 + 10k PEG 23 nM 59 pM 0,9 nM
cgGLP-28
SEC ID Nº: 22 + PEG de 30k 71 nM 0,1 nM 0,8 nM
cgGLP-29
SEC ID Nº: 22 + PEG ramificado de 40k 800 nM 0,15 nM 1 nM
HGEGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GCSGG-AMIDA (SEC ID
40
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REF INTERNA Nº
SECUENCIA CI50 humana CE50 humana CE50 deratón
Nº: 24)
mgGLP-15
SEC ID Nº: 24 + PEG de 20k 100 nM 0,2nM 1,8 nM
H[Aib]EGT FTSDV SSYLE [Aib]QAAK EFIAW LVKGR GCSG (SEC ID Nº: 25)
cgGLP-20
SEC ID Nº: 25 + mPEG de 20k 30 nM 99 pM 1,5 nM
Ejemplo 7
Resultados con compuestos de GLP-1 cíclico
5 Se realizaron experimentos in vitro para determinar la potencia y unión del receptor para una variedad de compuestos de GLP-1 en los que las cadenas laterales de ciertos aminoácidos se unieron para formar un anillo (una lactama cíclica). Se realizaron experimentos como se describe en el Ejemplo 2. Las secuencias de los compuestos cíclicos probados se muestran en la Tabla 6 junto con los resultados. Las cadenas laterales de los aminoácidos que
10 participaron en la formación de la lactama cíclica se muestran en negrita y subrayadas. De los compuestos enumerados en la Tabla 6, solo mgGLP-24 se pegiló.
Tabla 6
REF INTERNA Nº
SECUENCIA CI50 humana CE50 humana CE50 deratón
[Gly8]GLP1(7-37) ciclo[Glu14-Lys18]
HGEGT FTSDV SSYEE GQKAK EFIAW LVKGR G AMIDA (SEC ID Nº: 35) 12 pM 0,21 nM
[Gly8]GLP1(7-37) ciclo[Glu15-Lys19]
HGEGT FTSDV SSYLE GQAKK EFIAW LVKGR G AMIDA (SEC ID Nº: 36) 0,15 nM 66 pM
GLP1(7-37) ciclo[Glu15-Lys19; 27-31]
HGEGT FTSDV SSYLE GQAKK EFIAW LEKGR K AMIDA (SEC ID Nº: 277) indeterminada indeterminada
[Gly8]ciclo[2126]GLP1(7-37)amida
HGEGT FTSDV SSYLE GQAAKEFIAW LVKGR G AMIDA (SEC ID Nº: 42) 0,6 nM indeterminada
cicloE22-K26
HGEGT FTSDV SSYLE EQAAKEFIAW LVKGR G -AMIDA (SEC ID Nº: 30) 1,1 nM 9 pM 68 pM
mgGLP24
SEC ID Nº: 30 + mPEG de 20k 48 nM 0,25 nM 0,9 nM
cicloE22-026
HGEGT FTSDV SSYLE EQAAOEFIAW LVKGR G -AMIDA (SEC ID Nº: 69) 3,7 nM 51 pM 0,25 nM
GLP1(7-37) ciclo[Lys16-Glu20]
HGEGT FTSDV SSYLE KQAAEEFIAW LVKGR G AMIDA (SEC ID Nº: 159) 16 pM 0,1 nM
Gly8]GLP1(7-37) ciclo[Glu17-Lys21]
HGEGT FTSDV SSYLE GEAAKKFIAW LVKGR G AMIDA (SEC ID Nº: 38) 18 pM 0,17 nM
[Gly8]GLP1(7-37) ciclo[Glu18-Lys22]
HGEGT FTSDV SSYLE GQEAK EKIAW LVKGR G AMIDA (SEC ID Nº: 39) 0,8 nM indeterminada
O= ornitina = aa sin cadena lateral de CH2CH2CH2NH3
15 Ejemplo 8 Resultados con compuestos de GLP-1 que tienen extensión del extremo N
Se realizaron experimentos in vitro para determinar la potencia y unión del receptor para compuestos de GLP-1 que 20 tienen una extensión del extremo N. Se realizaron experimentos como se describe en el Ejemplo 2, y los resultados se resumen en la Tabla 7 a continuación. No se pegiló ninguno de los compuestos enumerados en la Tabla 7.
Tabla 7
REF INTERNA Nº
SECUENCIA CI50 humana CE50 humana CE50 deratón
A-GLP-1
A HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 247) 38 nM 0,2 nM 0,8 nM
G-GLP-1
G HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 248) 80 nM 1 nM 3 nM
P-GLP-1
P HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 249) 38 nM 0,2 nM 1 nM
S-GLP-1
S HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 250) 53 nM 0,4 nM 2 nM
T-GLP-1
T HAEGT FTSDV SSYLE GQAAK 53 nM 0,3 nM 2 nM
41
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EFIAW LVKGR (SEC ID Nº: 251)
V-GLP-1
V HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 252) 32 nM 0,2 nM 1 nM
MQ-GLP1
MQ HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 253) 64 nM 0,5 nM 3,0 nM
MR-GLP1
MR HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 254) 590 nM 8 nM 41 nM
MK-GLP1
MK HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 255) 760 nM 4 nM 12 nM
M-GLP1
M HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 256) 18 nM 86 pM 0,5 nM
KH-GLP1
MH HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 257) 350 nM 2 nM 11 nM
MHH-GLP1
MHH HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 258) 350 nM 1,0 nM 5 nM
MY-GLP1
MY HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 259) 57 nM 0,4 nM 1 nM
MI-GLP1
MI HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 260) 75 nM 0,6 nM 6 nM
' MD-GLP1
MD HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 261) 82 nM 0,3 nM 2 nM
ML-GLP1
ML HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 262) 160 nM 0,7 nM 6 nM
MN-GLP1
MN HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 263) 50 nM 0,3 nM 2 nM
ME-GLP1
ME HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 264) 95 nM 1 nM 4 nM
MW-GLP1
MW HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 265) 79 nM 0,8 nM 5 nM
MF-GLP1
MF HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 266) 180 nM 1 nM 6 nM
MM-GLP1
MM HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR (SEC ID Nº: 267) 100 nM 0,5 nM 3 nM
Ejemplo 9
Resultados in vivo -Efecto sobre los niveles de glucosa en sangre con el tiempo
5 Se probaron una variedad de diferentes compuestos de GLP-1, que incluyen representantes de las diferentes clases desveladas en el presente documento (por ejemplo, compuestos que tienen la estructura general de fórmulas I-IV descritas anteriormente), para su capacidad para afectar niveles de glucosa en sangre. En estos experimentos la glucosa en sangre se midió en ratones db/db como se describe en el Ejemplo 3.
10 La Figura 12 muestra la capacidad de cgGLP-17, cgGLP-18, cgGLP-19, mgGLP-09A (véanse las Tablas 4 y 5 para secuencias y tamaño y tipo de PEG) y mg-GLP-09A para reducir la glucosa en sangre durante un periodo de tiempo de 72 horas. Cada uno de estos compuestos redujo la glucosa en sangre con respecto al control, reduciendo cgGLP-19 la glucosa en sangre durante el periodo de tiempo más largo (se necesitaron 72 horas a una dosis de 10
15 ug/ratón para que los niveles de glucosa en el ratón volvieran a los niveles normales). Se realizó otro conjunto de experimentos con cgGLP-19, cgGLP-20, cgGLP-23, cgGLP-24 (véase la Tabla 5 para secuencias y tamaño y tipo de PEG). Se inyectaron 10 ug de compuesto de GLP-1 en cada ratón. Como se muestra en la Figura 13, estos cuatro compuestos de GLP-1 mostraron capacidad similar para reducir los niveles de glucosa en sangre con el tiempo, causando cada uno una disminución significativa en los niveles de glucosa en sangre durante un periodo de tiempo
20 de 48 horas.
Se realizaron otro conjunto de experimentos usando mgGLP-20, cgGLP-26, mgGLP-22 y mgGLP-24 (véanse las Tablas 5 y 6 para secuencias y tamaño y tipo de PEG). La dosificación fue 10 ug por ratón. Como se muestra en la Figura 14, aunque cada compuesto redujo los niveles de glucosa en sangre, lo hicieron de manera diferente. En este
25 ejemplo, mgGLP-20 y mgGLP-24 redujeron la glucosa durante el mayor periodo de tiempo. Con estos dos compuestos se necesitaron 72 horas para que los niveles de glucosa en sangre volvieran a los niveles normales.
Ejemplo 10
30 Reducción de la glucosa en sangre en un modo dependiente de la dosis
42
imagen33

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