NZ761754B2 - Acylated oxyntomodulin peptide analog - Google Patents
Acylated oxyntomodulin peptide analog Download PDFInfo
- Publication number
- NZ761754B2 NZ761754B2 NZ761754A NZ76175418A NZ761754B2 NZ 761754 B2 NZ761754 B2 NZ 761754B2 NZ 761754 A NZ761754 A NZ 761754A NZ 76175418 A NZ76175418 A NZ 76175418A NZ 761754 B2 NZ761754 B2 NZ 761754B2
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- New Zealand
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- seq
- compound
- peptide analog
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract 9
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 Chemical class C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 title abstract 3
- 101800001388 Oxyntomodulin Proteins 0.000 claims abstract 16
- 208000008589 Obesity Diseases 0.000 claims abstract 7
- 235000020824 obesity Nutrition 0.000 claims abstract 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 6
- 239000004971 Cross linker Substances 0.000 claims 16
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical group CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims 9
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims 7
- 125000000217 alkyl group Chemical group 0.000 claims 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 5
- 206010033307 Overweight Diseases 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 4
- 229920006395 saturated elastomer Polymers 0.000 claims 4
- 125000003277 amino group Chemical group 0.000 claims 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 125000001433 C-terminal amino-acid group Chemical group 0.000 claims 2
- 108010069514 Cyclic Peptides Proteins 0.000 claims 2
- 102000001189 Cyclic Peptides Human genes 0.000 claims 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- 150000003973 alkyl amines Chemical class 0.000 claims 2
- -1 aminobenzoyl Chemical group 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 150000003951 lactams Chemical group 0.000 claims 2
- 229960003104 ornithine Drugs 0.000 claims 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical group C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 claims 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 claims 1
- 229940126657 Compound 17 Drugs 0.000 claims 1
- 229940126639 Compound 33 Drugs 0.000 claims 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims 1
- 235000008206 alpha-amino acids Nutrition 0.000 claims 1
- 150000001413 amino acids Chemical group 0.000 claims 1
- 150000004982 aromatic amines Chemical class 0.000 claims 1
- 150000001576 beta-amino acids Chemical class 0.000 claims 1
- 229940125773 compound 10 Drugs 0.000 claims 1
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- 229940126543 compound 14 Drugs 0.000 claims 1
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- 229940126214 compound 3 Drugs 0.000 claims 1
- 229940125877 compound 31 Drugs 0.000 claims 1
- 229940125807 compound 37 Drugs 0.000 claims 1
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- 125000000524 functional group Chemical group 0.000 claims 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 claims 1
- ABABQFDOYCEIRS-UHFFFAOYSA-N piperidin-2-ylidenemethanone Chemical compound O=C=C1CCCCN1 ABABQFDOYCEIRS-UHFFFAOYSA-N 0.000 claims 1
- 150000003573 thiols Chemical group 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 abstract 1
- 102400000321 Glucagon Human genes 0.000 abstract 1
- 108060003199 Glucagon Proteins 0.000 abstract 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 abstract 1
- 102400000319 Oxyntomodulin Human genes 0.000 abstract 1
- 102100040918 Pro-glucagon Human genes 0.000 abstract 1
- 230000004913 activation Effects 0.000 abstract 1
- 230000009977 dual effect Effects 0.000 abstract 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 abstract 1
- 229960004666 glucagon Drugs 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- A61K38/26—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
-
- 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
-
- 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
-
- 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
Abstract
The present invention relates to a novel peptide analog of acylated oxyntomodulin and a pharmaceutical composition for preventing and treating obesity or overweightness, or diabetes accompanied by obesity and overweightness, containing the same, wherein the peptides have dual activation efficacy on receptors of GLP-1/glucagon and increased in vivo half-life, which are superior to those of natural oxyntomodulin, and the pharmaceutical composition containing the same is effective in the treatment of metabolic diseases such as obesity and diabetes.
Claims (19)
1.[Claim 1] An oxyntomodulin peptide analog of the following formula I: His-X1-Gln-Gly-Thr-Phe-Thr-Ser-X2-X3-X4-X5-X6-X7-X8-X9-Arg-Arg-Ala-X10-Asp-Phe-ValGln-Trp-Leu-X11-X12-X13-X14-X15-X16 (SEQ ID NO.49), wherein: X1 is Aib (aminoisobutyric acid); X2 is Asp; X3 is Tyr or Z; X4 is Ser; X5 is Lys; X6 is Tyr; X7 is Leu; X8 is Asp; X9 is Ser, Aib (aminoisobutyric acid) or Z; X10 is Gln or Z; X11 is Met or Leu; X12 is Asn or Arg; X13 is Thr or Ala; X14 is Lys; X15 is absent; X16 is absent; C-terminal amino acid may optionally be amidated, wherein one of X3, X9, X10, is Z; Z is modified Lys to which Z1-Z2 of the following formulas is attached; Z1 is Formula (1); and (1) Z2 is Formula (3); (3) wherein * of Formula (1) is directly bound to a side chain of Lys, and wherein ** of Formula (1) and ** of Formula (3) are a bond between Z1 and Z2.
2.[Claim 2] The oxyntomodulin peptide analog of claim 1, wherein X11 is Leu, X12 is Arg, and X13 is Ala.
3.[Claim 3] 42 The oxyntomodulin peptide analog of claim 1, wherein n2 of Formula (1) is 1.
4.[Claim 4] The oxyntomodulin peptide analog of claim 1, wherein said peptide analog is Compound 2(SEQ ID NO. 3), Compound 3(SEQ ID NO. 4), Compound 6(SEQ ID NO. 7), Compound 9(SEQ ID NO. 10), Compound 10(SEQ ID NO. 11), Compound 12(SEQ ID NO. 13), Compound 15(SEQ ID NO. 16), Compound 16(SEQ ID NO. 17), Compound 17(SEQ ID NO. 18), or Compound 18(SEQ ID NO. 19).
5.[Claim 5] An oxyntomodulin peptide analog having an intramolecular cross-link at X19 and X20 of the amino acid sequence of the following Formula II: His-X17-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X18- Ser-Lys-Tyr-Leu-Asp-X19-Arg-Arg-Ala-X20-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys (SEQ ID NO.53), wherein: X17 is Aib (Aminoisobutyric acid); X18 is Z; X19 is Asp, Glu, Cys, Hcy (Homocysteine), Lys or Orn (Ornithine); X20 is Asp, Glu, Cys, Hcy (Homocysteine), Lys or Orn (Ornithine); wherein the intramolecular cross-link at X19 and X20 form a cyclic peptide via intramolecular bond or via a cross-linker, said cyclic peptide has a lactam ring formed by amide bond between two residues at X19 and X20, or a cross-linked ring formed by cross-linker bond between two residues at X19 and X20; C-terminal amino acid may optionally be amidated; and Z is modified Lys to which Z1-Z2 of the following formulas is attached; Z1 is Formula (1); and (1) Z2 is Formula (3); (3) wherein * of Formula (1) is directly bound to a side chain of Lys, and wherein ** of Formula (1) and ** of Formula (3) are a bond between Z1 and Z2.
6.[Claim 6] The oxyntomodulin peptide analog of claim 5, wherein: the intramolecular bond between X19 and X20 is an intramolecular lactam ring when X19 and X20 are Asp or Glu and Lys or Orn, respectively; or Lys or Orn and Asp or Glu, respectively.
7.[Claim 7] The oxyntomodulin peptide analog of claim 5, wherein X19 and X20 are Cys or Hcy and Cys or Hcy, respectively, and a cross-linker bonds to the thiol functional group at both Cys or Hcy side chains to form a ring; and said cross-linker is C1-C6 linear or branched chain alkyl, C3-C8 saturated or unsaturated 43 cycloalkyl, C6-C10 aryl, C5-C12 heteroaryl, or C5-C12 fused heterocyclic aryl.
8.[Claim 8] The oxyntomodulin peptide analog of claim 7, wherein the cross-linker is selected from the group consisting of , , , , , , and , wherein R is hydrogen or C1-C6 linear or branched alkyl chain.
9.[Claim 9] The oxyntomodulin peptide analog of claim 5, wherein X19 and X20 are Asp or Glu and Asp or Glu, respectively, and a cross-linker forms an amide bond to the carboxylic group at both Asp or Glu side chains to form a ring; and said cross-linker is di-amino C1-C6 linear or branched alkyl chain, di-amino C3-C8 saturated or unsaturated cycloalkyl, aminopiperidine, piperazine, di-amino C6-C10 aryl, di-amino C5- C12 heteroaryl, or di-amino C5-C12 fused heterocyclic aryl.
10.[Claim 10] The oxyntomodulin peptide analog of claim 9, wherein the cross-linker is selected from the group consisting of , , , , , , , , and , wherein R is hydrogen or C1-C6 linear or branched alkyl chain.
11.[Claim 11] The oxyntomodulin peptide analog of claim 5, wherein X19 and X 20 are each Lys or Orn and Lys or Orn, respectively; a cross-linker forms an amide bond with the amine group at both Lys or Orn side chains to form a ring; and said cross-linker is di-carbonyl C1-C6 linear or branched alkyl chain, di-carbonyl C3- C8 saturated or unsaturated cycloalkyl, di-carbonyl C6-C10 aryl, di-carbonyl C5-C12 heteroaryl, or di-carbonyl C5-C12 fused heterocyclic aryl.
12.[Claim 12] The oxyntomodulin peptide analog of claim 11, wherein 44 the cross-linker is selected from the group consisting of , , , , , and ; and R is hydrogen or C1-C6 linear or branched alkyl chain.
13.[Claim 13] The oxyntomodulin peptide analog of claim 5, wherein: X19 and X20 are Asp or Glu and Lys or Orn, respectively; or are Lys or Orn and Asp or Glu, respectively; and a cross-linker forms an amide bond between the carboxyl group of Asp or Glu side chain and the amine functional group of the cross-linker; and/or the amine group at Lys or Orn side chain is connected via an amide bond to the carboxyl functional group of the cross-linker to form a ring; and said cross-linker is either an alpha amino acid selected from the group consisting of Gly, Val, Leu, and Ile; a beta amino acid; carbonyl C1-C6 linear or branched alkylamine; carbonyl C3- C8 saturated or unsaturated alkylamine; carbonyl piperidine; aminobenzoyl; or one of carbonyl C6-C10 arylamine, carbonyl C5-C12 heteroarylamine, or carbonyl C5-C12 fused heterocyclic arylamine.
14.[Claim 14] The oxyntomodulin peptide analog of claim 13, wherein the cross-linker is selected from the group consisting of , , , , , , , , , and ; and R is hydrogen or C1-C6 linear or branched alkyl chain.
15.[Claim 15] The oxyntomodulin peptide analog of claim 5, wherein said peptide analog is Compound 14(SEQ ID NO. 15), Compound 19(SEQ ID NO. 20), Compound 20(SEQ ID NO. 21), Compound 21(SEQ ID NO. 22), Compound 22(SEQ ID NO. 23), Compound 23(SEQ ID NO. 24), Compound 27(SEQ ID NO. 28), Compound 29(SEQ ID NO. 30), Compound 30(SEQ ID NO. 31), Compound 31(SEQ ID NO. 32), Compound 32(SEQ ID NO. 33), Compound 33(SEQ ID NO. 34), Compound 34(SEQ ID NO. 35), Compound 35(SEQ ID NO. 36), Compound 45 36(SEQ ID NO. 37), Compound 37(SEQ ID NO. 38), or Compound 38(SEQ ID NO. 39).
16.[Claim 16] A pharmaceutical composition comprising the peptide analog of one of claims 1-4 and pharmaceutically acceptable excipients for the prevention or treatment of conditions caused by or characterized by obesity or overweight.
17.[Claim 17] A pharmaceutical composition comprising the peptide analog of one of claims 1-4 and pharmaceutically acceptable excipients for the prevention or treatment of non-insulindependent diabetes accompanying obesity or overweight.
18.[Claim 18] A pharmaceutical composition comprising the peptide analog of one of claims 5-15 and pharmaceutically acceptable excipients for the prevention or treatment of conditions caused by or characterized by obesity or overweight.
19.[Claim 19] A pharmaceutical composition comprising the peptide analog of one of claims 5-15 and pharmaceutically acceptable excipients for the prevention or treatment of non-insulindependent diabetes accompanying obesity or overweight
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20170103798 | 2017-08-16 | ||
| PCT/KR2018/009425 WO2019035672A1 (en) | 2017-08-16 | 2018-08-16 | Acylated oxyntomodulin peptide analog |
| KR1020180095717A KR102230363B1 (en) | 2017-08-16 | 2018-08-16 | Acylated oxyntomodulin analogues |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ761754A NZ761754A (en) | 2023-09-29 |
| NZ761754B2 true NZ761754B2 (en) | 2024-01-04 |
Family
ID=
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