US20210363213A1 - Glucagon-glp-1-gip triple agonist compounds - Google Patents
Glucagon-glp-1-gip triple agonist compounds Download PDFInfo
- Publication number
- US20210363213A1 US20210363213A1 US17/388,328 US202117388328A US2021363213A1 US 20210363213 A1 US20210363213 A1 US 20210363213A1 US 202117388328 A US202117388328 A US 202117388328A US 2021363213 A1 US2021363213 A1 US 2021363213A1
- Authority
- US
- United States
- Prior art keywords
- aib
- peg3
- isoglu
- ser
- hexadecanoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 104
- 239000013559 triple agonist Substances 0.000 title claims description 46
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 13
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 46
- 206010012601 diabetes mellitus Diseases 0.000 claims description 35
- -1 His Chemical compound 0.000 claims description 33
- 208000008589 Obesity Diseases 0.000 claims description 32
- 239000008280 blood Substances 0.000 claims description 31
- 210000004369 blood Anatomy 0.000 claims description 31
- 235000020824 obesity Nutrition 0.000 claims description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 29
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 24
- 101100353123 Rattus norvegicus Ppp1r15a gene Proteins 0.000 claims description 23
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 22
- 208000035475 disorder Diseases 0.000 claims description 22
- 239000012453 solvate Substances 0.000 claims description 19
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 16
- 239000008103 glucose Substances 0.000 claims description 16
- 230000001965 increasing effect Effects 0.000 claims description 16
- 150000007523 nucleic acids Chemical class 0.000 claims description 15
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 15
- 102000039446 nucleic acids Human genes 0.000 claims description 14
- 108020004707 nucleic acids Proteins 0.000 claims description 14
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 13
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000006850 spacer group Chemical group 0.000 claims description 10
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 230000000770 proinflammatory effect Effects 0.000 claims description 9
- 230000003331 prothrombotic effect Effects 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 8
- 208000001280 Prediabetic State Diseases 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 230000000923 atherogenic effect Effects 0.000 claims description 6
- 230000036772 blood pressure Effects 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 5
- 238000008214 LDL Cholesterol Methods 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 5
- 210000000988 bone and bone Anatomy 0.000 claims description 5
- 208000029078 coronary artery disease Diseases 0.000 claims description 5
- 208000020694 gallbladder disease Diseases 0.000 claims description 5
- 208000004104 gestational diabetes Diseases 0.000 claims description 5
- 208000030613 peripheral artery disease Diseases 0.000 claims description 5
- 230000003248 secreting effect Effects 0.000 claims description 5
- 150000003626 triacylglycerols Chemical class 0.000 claims description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- 208000010392 Bone Fractures Diseases 0.000 claims description 4
- 108010074051 C-Reactive Protein Proteins 0.000 claims description 4
- 102100032752 C-reactive protein Human genes 0.000 claims description 4
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 4
- 108010049003 Fibrinogen Proteins 0.000 claims description 4
- 102000008946 Fibrinogen Human genes 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 4
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 claims description 4
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- 210000001367 artery Anatomy 0.000 claims description 4
- 229940012952 fibrinogen Drugs 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 201000002859 sleep apnea Diseases 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 101100533230 Caenorhabditis elegans ser-2 gene Proteins 0.000 claims description 2
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- SBVPYBFMIGDIDX-SRVKXCTJSA-N Pro-Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H]2NCCC2)CCC1 SBVPYBFMIGDIDX-SRVKXCTJSA-N 0.000 claims 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 29
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 abstract description 24
- 108010063919 Glucagon Receptors Proteins 0.000 abstract description 21
- 102000051325 Glucagon Human genes 0.000 abstract description 18
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 abstract description 18
- 229960004666 glucagon Drugs 0.000 abstract description 18
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 abstract description 17
- 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 description 17
- 239000000556 agonist Substances 0.000 abstract description 16
- 102100025892 Complement C1q tumor necrosis factor-related protein 1 Human genes 0.000 abstract 1
- 102100040918 Pro-glucagon Human genes 0.000 description 36
- 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 description 29
- 150000001413 amino acids Chemical class 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 26
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 24
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 24
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 22
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 17
- 102100040890 Glucagon receptor Human genes 0.000 description 16
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 230000037396 body weight Effects 0.000 description 14
- 108060003199 Glucagon Proteins 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 125000000539 amino acid group Chemical group 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 102000004196 processed proteins & peptides Human genes 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 239000002243 precursor Substances 0.000 description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 102000015779 HDL Lipoproteins Human genes 0.000 description 8
- 108010010234 HDL Lipoproteins Proteins 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 230000002641 glycemic effect Effects 0.000 description 8
- 125000005647 linker group Chemical group 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical group CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000037406 food intake Effects 0.000 description 6
- 235000012631 food intake Nutrition 0.000 description 6
- 201000001421 hyperglycemia Diseases 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 101000886868 Homo sapiens Gastric inhibitory polypeptide Proteins 0.000 description 5
- 108010007622 LDL Lipoproteins Proteins 0.000 description 5
- 102000007330 LDL Lipoproteins Human genes 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 102000050325 human granulocyte inhibitory Human genes 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000003914 insulin secretion Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 229940044601 receptor agonist Drugs 0.000 description 5
- 239000000018 receptor agonist Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 4
- 108010016626 Dipeptides Proteins 0.000 description 4
- 108010011459 Exenatide Proteins 0.000 description 4
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 4
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 4
- 108010058003 Proglucagon Proteins 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000003466 anti-cipated effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000002843 carboxylic acid group Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229960001519 exenatide Drugs 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 239000000859 incretin Substances 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 150000003456 sulfonamides Chemical class 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- 0 *S(=O)(=O)NC(=O)C(C)C.CC(C)C(=O)NO.CC(C)C1=C(O)C(=O)C1=O.CC(C)C1=NN=NN1 Chemical compound *S(=O)(=O)NC(=O)C(C)C.CC(C)C(=O)NO.CC(C)C1=C(O)C(=O)C1=O.CC(C)C1=NN=NN1 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- DZOJHYJJSULYFJ-UHFFFAOYSA-N C.C.CC(C)C[V][Y]C(C)C Chemical compound C.C.CC(C)C[V][Y]C(C)C DZOJHYJJSULYFJ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000003491 cAMP production Effects 0.000 description 3
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=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](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)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)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000004130 lipolysis Effects 0.000 description 3
- 150000004668 long chain fatty acids Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 229960003105 metformin Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 3
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- YWWVWXASSLXJHU-AATRIKPKSA-N (9E)-tetradecenoic acid Chemical compound CCCC\C=C\CCCCCCCC(O)=O YWWVWXASSLXJHU-AATRIKPKSA-N 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- OZHGQKONZFIYAR-ZXEZTWSKSA-N CC(C)C(=O)CC[C@H](CC(=O)CCCCCCCCCCCCCCCCC(=O)O)C(=O)O.CC(C)C(=O)COCCOCCCC(=O)COCCOCCNC(=O)CC[C@H](CC(=O)CCCCCCCCCCCCCCCCC(=O)O)C(=O)O.CC(C)C(=O)COCCOCCCC(=O)COCCOCCNC(=O)CC[C@H](CC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)C(=O)O.CCCCCCCCCCCCCCCC(=O)C[C@@H](CCC(=O)C(C)C)C(=O)O.CCCCCCCCCCCCCCCCCC(=O)C[C@@H](CCC(=O)NCCOCCOCC(=O)CCCOCCOCC(=O)C(C)C)C(=O)O.CCCCCCCCCCCCCCCCCC(=O)C[C@@H](CN)C(=O)NCCOCCOCC(=O)CCCOCCOCC(=O)C(C)C.CCCCCCCCCCCCCCCCCCCC(=O)C[C@@H](CCC(=O)NCCOCCOCC(=O)CCCOCCOCC(=O)C(C)C)C(=O)O Chemical compound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description 2
- 150000008574 D-amino acids Chemical class 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)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](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)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=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 2
- 108010019598 Liraglutide Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102400000319 Oxyntomodulin Human genes 0.000 description 2
- 101800001388 Oxyntomodulin Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 2
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000002424 anti-apoptotic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 125000002993 cycloalkylene group Chemical group 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(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]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- 230000014101 glucose homeostasis Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229960002701 liraglutide Drugs 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 150000004667 medium chain fatty acids Chemical class 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 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(=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 description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical compound NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 2
- 208000001797 obstructive sleep apnea Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000863 peptide conjugate Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- GOPWHXPXSPIIQZ-FQEVSTJZSA-N (4s)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 GOPWHXPXSPIIQZ-FQEVSTJZSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 1
- DGRJZSGHEKZYHP-UHFFFAOYSA-N 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetic acid Chemical compound NCCOCCOCCOCC(O)=O DGRJZSGHEKZYHP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- CXISPYVYMQWFLE-VKHMYHEASA-N Ala-Gly Chemical compound C[C@H]([NH3+])C(=O)NCC([O-])=O CXISPYVYMQWFLE-VKHMYHEASA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 1
- NHDZESQHWMKRPE-UHFFFAOYSA-N C.C.CCC Chemical compound C.C.CCC NHDZESQHWMKRPE-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- IJCUGVMSBASPAS-UHFFFAOYSA-N CC(C)C1=CC=C(C(C)C)C=C1.CC(C)N1CCN(C(C)C)CC1 Chemical compound CC(C)C1=CC=C(C(C)C)C=C1.CC(C)N1CCN(C(C)C)CC1 IJCUGVMSBASPAS-UHFFFAOYSA-N 0.000 description 1
- ROMNPSGQFOMZEQ-UHFFFAOYSA-N CC(C)CC(CC(=O)O)NC(C)C.CC(C)CCC(NC(C)C)C(=O)O Chemical compound CC(C)CC(CC(=O)O)NC(C)C.CC(C)CCC(NC(C)C)C(=O)O ROMNPSGQFOMZEQ-UHFFFAOYSA-N 0.000 description 1
- BDNORIACWVVWLT-UHFFFAOYSA-N CC(C)CCCOCCOCC(=O)C(C)C Chemical compound CC(C)CCCOCCOCC(=O)C(C)C BDNORIACWVVWLT-UHFFFAOYSA-N 0.000 description 1
- CFZMWSRBRLAOGK-UHFFFAOYSA-N CC(C)C[V][Y]C(C)C Chemical compound CC(C)C[V][Y]C(C)C CFZMWSRBRLAOGK-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 1
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 102000006419 Glucagon-Like Peptide Receptors Human genes 0.000 description 1
- 108010083749 Glucagon-Like Peptide Receptors Proteins 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- VPZXBVLAVMBEQI-VKHMYHEASA-N Glycyl-alanine Chemical compound OC(=O)[C@H](C)NC(=O)CN VPZXBVLAVMBEQI-VKHMYHEASA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 101000788682 Homo sapiens GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 description 1
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 1
- 101000581402 Homo sapiens Melanin-concentrating hormone receptor 1 Proteins 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010056997 Impaired fasting glucose Diseases 0.000 description 1
- 108010089308 Insulin Detemir Proteins 0.000 description 1
- 108010057186 Insulin Glargine Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- DEFJQIDDEAULHB-IMJSIDKUSA-N L-alanyl-L-alanine Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(O)=O DEFJQIDDEAULHB-IMJSIDKUSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241000270322 Lepidosauria Species 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 229940086609 Lipase inhibitor Drugs 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100027375 Melanin-concentrating hormone receptor 1 Human genes 0.000 description 1
- 102100023724 Melanocortin receptor 4 Human genes 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 108010079364 N-glycylalanine Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010088847 Peptide YY Proteins 0.000 description 1
- 102100029909 Peptide YY Human genes 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000035554 Proglucagon Human genes 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- WOUIMBGNEUWXQG-VKHMYHEASA-N Ser-Gly Chemical compound OC[C@H](N)C(=O)NCC(O)=O WOUIMBGNEUWXQG-VKHMYHEASA-N 0.000 description 1
- LDEBVRIURYMKQS-WISUUJSJSA-N Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](N)CO LDEBVRIURYMKQS-WISUUJSJSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 108010056243 alanylalanine Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 description 1
- 229940112930 apidra Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 208000012696 congenital leptin deficiency Diseases 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000035611 feeding Effects 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- ZEKANFGSDXODPD-UHFFFAOYSA-N glyphosate-isopropylammonium Chemical compound CC(C)N.OC(=O)CNCP(O)(O)=O ZEKANFGSDXODPD-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- 102000056448 human GLP1R Human genes 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(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](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)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=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 108700039926 insulin glulisine Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000008863 intramolecular interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- UGOZVNFCFYTPAZ-IOXYNQHNSA-N levemir Chemical compound CCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=2C=CC=CC=2)C(C)C)CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)CSSC[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC2=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 UGOZVNFCFYTPAZ-IOXYNQHNSA-N 0.000 description 1
- 229940102988 levemir Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000023187 negative regulation of glucagon secretion Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- NNNVXFKZMRGJPM-KHPPLWFESA-N sapienic acid Chemical compound CCCCCCCCC\C=C/CCCCC(O)=O NNNVXFKZMRGJPM-KHPPLWFESA-N 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical class OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 150000004669 very long chain fatty acids Chemical class 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to compounds having agonist activity at the glucagon, GIP and GLP-1 receptors, and to their use in the treatment of metabolic disorders.
- CVD cardiovascular diseases
- obstructive sleep apnea obstructive sleep apnea
- stroke peripheral artery disease
- microvascular complications CAD
- osteoarthritis CAD
- CVD cardiovascular diseases
- Many have additional cardiovascular risk factors including high/aberrant LDL and triglycerides and low HDL.
- Cardiovascular disease accounts for about 50% of the mortality in people with diabetes, and the morbidity and mortality rates relating to obesity and diabetes underscore the medical need for efficacious treatment options.
- Pre-proglucagon is a 158 amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP-1 or GLP1), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM), which are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake.
- GLP-1 or GLP1 glucagon-like peptide-1
- GLP-2 glucagon-like peptide-2
- OXM oxyntomodulin
- Glucagon is a 29-amino acid peptide that corresponds to amino acids 33 through 61 of pre-proglucagon, while GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of pre-proglucagon.
- glucagon a hormone produced by the pancreas, signals the liver to break down glycogen and release glucose, causing blood glucose levels to rise toward a normal level.
- glucagon reduces body weight probably through inhibition of food intake and stimulation of energy expenditure and/or lipolysis.
- GLP-1 has different biological activities compared to glucagon. Its actions include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. GLP-1 has been shown to reduce hyperglycemia (elevated glucose levels) in diabetic patients.
- Exendin-4 a peptide from lizard venom that shares about 50% amino acid identity with GLP-1, activates the GLP-1 receptor and likewise has been shown to reduce hyperglycemia in diabetic patients.
- Glucose-dependent insulinotropic polypeptide is a 42-amino acid gastrointestinal regulatory peptide that, like GLP-1, stimulates insulin secretion from pancreatic ⁇ (beta) cells in the presence of elevated blood glucose levels. It is derived by proteolytic processing from a 133-amino acid precursor, preproGlP.
- glucagon-GLP-1 dual acting receptor agonists are currently in pre-clinical development (see, e.g., WO2011/006497).
- glucagon-GLP-1 dual agonists are associated with more profound and sustained body weight loss in animal models on top of the improvements in glycemic control.
- glucagon based drugs may have promise for the treatment of type 2 diabetes mellitus and/or obesity.
- Incretins are gastrointestinal hormones that regulate blood glucose by enhancing glucose-stimulated insulin secretion (Drucker, D J and Nauck, M A, Lancet 368: 1696-705 (2006)).
- Two of the above mentioned peptides are known as incretins: GLP-1 and GIP.
- the discovery of the incretins has led to the development of two new classes of drugs for the treatment of diabetes mellitus.
- GLP-1 receptor agonists and small molecule compounds (oral DPP-4 inhibitors) that inhibit enzymatic inactivation of both endogenous GLP-1 and GIP
- GLP-1 receptor agonists ByettaTM, BydureonTM LixisenatideTM and LiraglutideTM
- DPP-4 inhibitors JanuviaTM GalvusTM OnglyzaTM and TrajentaTM
- the two peptides also have long term effects.
- GLP-1 R agonists protect pancreatic ⁇ -cells by inhibiting apoptosis and enhancing proliferation. For instance, the study by Farilla et al.
- GLP-1 had anti-apoptotic effects in human islets (Farilla, L, Endocrinology 144: 5149-58 (2003)). Such effects have not been reported for GIP until recently.
- Weidenmaier et al. reported that a DPP-4 resistant GIP analogue has anti-apoptotic effects (Weidenmaier, S D, PLOS One 5(3): e9590 (2010)).
- the combination of the GLP-1 receptor agonist Liraglutide and an acylated GIP analogue show superior effects compared to treatment with Liraglutide or GIP analogue alone (Gault, V A, Clinical Science 121: 107-117 (2011)).
- glucagon By combining glucagon, GLP-1 and GIP receptor agonism in novel inventive peptides it is anticipated that superior glycemic control and body weight loss can be achieved.
- Such peptides are likely to have strong incretin actions and improved ⁇ -cell preservation from the GLP-1 and GIP components, and have improved body weight loss from all three components by stimulating energy expenditure, lipolysis and reducing food intake.
- the present invention concerns Glucagon-GLP-1-GIP triple agonists (referred to in this specification as “triple agonists”) which comprise one or more substitutions as compared to wild-type glucagon and which may have the property of an altered, preferably increased GIP and GLP-1 receptor activity, e.g. as assessed in in vitro efficacy assays.
- triple agonists Glucagon-GLP-1-GIP triple acting receptor agonists are superior to existing and marketed GLP-1 analogues because the triple agonists offer improved glycemic control, possible islet and ⁇ -cell preservation and enhanced body weight loss.
- the Glucagon-GLP-1-GIP triple agonists could be used as therapeutics for both type 2 diabetes mellitus, obesity and related disorders.
- the invention provides a triple agonist having the general formula I:
- R 1 is H— (i.e., hydrogen), C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
- X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;
- X10 is Tyr or Leu
- X12 is Lys, Ile or ⁇
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Ser, Glu, Lys or ⁇
- X17 is Lys or ⁇
- X19 is Gln or Ala
- X20 is Lys, His, Arg or ⁇ ;
- X21 is Ala, Asp or Glu
- X23 is Val or Ile
- X24 is Asn, Glu or ⁇ ;
- X27 is Leu, Glu or Val
- X28 is Ala, Ser, Arg or ⁇ ;
- X29 is Aib, Ala, Gln or Lys
- X30 is Lys, Gly, or is absent
- Y1 is (SEQ ID NO: 53) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, (SEQ ID NO: 54) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, (SEQ ID NO: 55) Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, (SEQ ID NO: 56) Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, (SEQ ID NO: 57) Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or (SEQ ID NO: 58) Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, or is absent;
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent
- R 2 is —NH 2 or —OH
- ⁇ is present at one of positions X12, X16 and X17.
- the compound contains only one residue ⁇ , which may be present at any one of positions X12, X16, X17, X20, X24 or X28. For example, it may be present at one of X12, X16 and X17.
- the compound may possess one or more of the following sets of residues:
- L27, R28, and A29 L27, S28, and A29; L27, A28, and Q29; E27, S28, and A29; or V27, and A28, and Aib29;
- Positions 1 to 29 may have the sequence
- positions 1 to 29 may differ at up to 4 positions, e.g. at 1, 2, 3 or 4 positions, from any of the specific sequences shown above, within the constraints of Formula I.
- positions 1 to 29 may differ at up to 4 positions, e.g. at 1, 2, 3 or 4 positions from one of the following sequences:
- Positions 1 to 29 may have the sequence:
- the peptide backbone of Formula I may have the sequence:
- the peptide backbone sequence may differ at up to 5 positions from one of the sequences shown above, within the constraints of Formula I.
- a sequence satisfying the definition of Y1 is regarded as a single position.
- the compound differs from the reference sequence at only 4 positions in X1 to X29.
- one of those positions is generally X30 or Y1.
- the peptide backbone sequence may differ at up to 5 positions from one of the sequences:
- the peptide backbone of Formula I may have the sequence:
- Certain of the Y1 groups when present, may provide increased stability in vivo, e.g. in serum, and so may contribute to the half life of the GIP analogue. Without wishing to be bound by theory, it is believed that these groups may help to stabilize the three dimensional conformation of the molecule and/or provide resistance to proteolytic degradation.
- the Y1 sequences Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:53), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 54), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 55), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 56), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 57) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 58) have homology with a C-terminal portion of the Exendin-4 molecule and appear to contribute to the stability of the molecule without concomitantly providing significant levels of GLP-1 agonist activity.
- the invention further provides a nucleic acid encoding a peptide having the sequence X1-X30 of Formula I.
- an expression construct also known as an expression vector
- the invention also provides a host cell comprising a nucleic acid or expression construct and capable of expressing, and optionally secreting, the peptide.
- the peptide may itself be a compound of the invention, e.g. when the peptide contains only naturally occurring amino acids (i.e. proteinogenic amino acids), does not contain a residue ⁇ , and where R 1 and R 2 are H— and —OH respectively.
- the peptide may be a precursor of a compound of the invention.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a carrier, preferably a pharmaceutically acceptable carrier.
- the triple agonist may, for example, be a pharmaceutically acceptable acid addition salt.
- the pharmaceutical composition may be formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said triple agonist.
- the invention further provides a therapeutic kit comprising a triple agonist as described herein, and a device comprising a triple agonist as described herein.
- the invention further provides a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of medical treatment, e.g. for use in the treatment and/or prevention of a metabolic disorder.
- the invention further provides the use of a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment and/or prevention of a metabolic disorder.
- the invention further provides a method of prevention and or/treatment of a metabolic disorder in a subject, comprising administering a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, to the subject.
- the metabolic disorder may be diabetes or a diabetes related disorder, or obesity or an obesity related disorder.
- diabetes or a diabetes related disorder, or obesity or an obesity related disorder.
- the link between obesity and diabetes is well known, so these conditions are not necessarily separate or mutually exclusive.
- Diabetes related disorders include insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorders and combinations thereof.
- Diabetes related disorders also include atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or conditions associated with atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state and a proinflammatory state.
- Bone related disorders include, but are not limited to osteoporosis and increased risk of bone fracture.
- the blood fat disorder may be selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, and plaque buildup in artery walls, or a combination thereof.
- the prothrombotic state may be selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood.
- the proinflammatory state may be an elevated C-reactive protein level in the blood.
- Obesity related disorders include obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or may be associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a combination thereof.
- patient may be used interchangeably and refer to either a human or a non-human animal.
- mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).
- livestock animals e.g., bovines, porcines
- companion animals e.g., canines, felines
- rodents e.g., mice and rats.
- solvate in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (in casu, a peptide conjugate or pharmaceutically acceptable salt thereof according to the invention) and a solvent.
- the solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid.
- a solvate is normally referred to as a hydrate.
- agonist refers to a substance (ligand) that activates the receptor type in question.
- sequences disclosed herein are sequences incorporating an “H—” moiety at the amino terminus (N-terminus) of the sequence, and either an “—OH” moiety or an “—NH 2 ” moiety at the carboxy terminus (C-terminus) of the sequence.
- an “H—” moiety at the N-terminus of the sequence in question indicates a hydrogen atom (i.e. R 1 ⁇ H—), corresponding to the presence of a free primary or secondary amino group at the N-terminus
- an “—OH” or an “—NH 2 ” moiety at the C-terminus of the sequence i.e. R 2 ⁇ —OH or —NH 2
- R 1 groups are possible at the N-terminus, including pyroglutamic acid (pGlu; (S)-( ⁇ )-2-pyrrolidone-5-carboxylic acid), C 1-4 alkyl, acetyl, formyl, benzoyl and trifluoroacetyl.
- pGlu pyroglutamic acid
- S S-( ⁇ )-2-pyrrolidone-5-carboxylic acid
- C 1-4 alkyl acetyl, formyl, benzoyl and trifluoroacetyl.
- the compounds described herein are Glucagon-GIP-GLP 1 dual receptor agonists. That is to say, they have agonist activity at all three of the glucagon receptor, the GIP receptor and the GLP-1 receptor.
- agonist refers to a substance (ligand) that is capable of binding to a particular receptor and activating signaling by that receptor.
- a GIP receptor agonist is capable of binding to the GIP receptor (designated GIP-R) and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca 2+ release.
- Agonist activity at the GIP receptor may therefore be measured by assessing GIP receptor signalling, which may, for example, be measured via cAMP production or Ca 2+ release.
- the cDNA sequence encoding the human GIP receptor has GenBank accession no. BC101673.1 (GI:75516688).
- the encoded amino acid sequence (including signal peptide) is:
- the compounds have agonist activity at the GLP-1 receptor (GLP-1-R), i.e. they are capable of binding to the GLP-1 receptor and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca 2+ release.
- Agonist activity at the GLP-1 receptor may therefore be measured by assessing GLP-1 receptor signalling, which may, for example, be measured via cAMP production or Ca 2+ release.
- the GLP-1 receptor may have the sequence of the human glucagon-like peptide 1 receptor (GLP-1 R) having primary accession number P43220.
- the precursor protein (including signal peptide) has primary accession number NP_002053.3; GI:166795283 and has sequence:
- the compounds have agonist activity at the glucagon receptor (Glu-R), i.e. they are capable of binding to the glucagon receptor and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca 2+ release.
- Agonist activity at the glucagon receptor may therefore be measured by assessing glucagon receptor signalling, which may, for example, be measured via cAMP production or Ca 2+ release.
- the glucagon receptor may have the sequence of the human glucagon receptor (Glu-R) having primary accession number P47871.
- the precursor protein (including signal peptide) has primary accession number NP_000151.1; GI:4503947, and has the sequence:
- the compounds of the present invention have at least one GIP, one glucagon, and one GLP-1 biological activity, in particular in treatment of metabolic diseases such as diabetes and obesity. This can be assessed, e.g., in in vivo assays, for example as described in the examples, in which the blood glucose level or another biological activity is determined after a test animal has been treated or exposed to a triple agonist.
- compounds of the invention may be capable of improving glycaemic control when adminstered to a diabetic subject. Additionally or alternatively, they may be capable of reducing body weight when administered to an overweight or obese subject. In either case, the effect may be superior to that obtained with an equivalent quantity (by mass, or molar ratio) of wild type human GIP or GLP-1 in comparable subjects when given according to a comparable dosing regime.
- Activity in in vitro assays may also be used as a measure of the compounds' activity.
- the compounds typically have activity at the glucagon, GLP-1 and GIP receptors (designated GCG-R, GLP-1-R and GIP-R respectively).
- EC 50 values may be used as a numerical measure of agonist potency at a given receptor.
- An EC 50 value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay.
- a compound having EC 50 [GLP-1R] lower than the EC 50 [GLP-1 R] of native GIP in a particular assay may be considered to have higher potency at the GLP-1R than GIP.
- the EC 50 GLP-1-R and/or EC 50 GIP-R and/or EC 50 GCG-R is below 1.0 nM, below 0.9 nM, below 0.8 nM, below 0.7 nM, below 0.6 nM, below 0.5 nM, below 0.4 nM, below 0.3 nM, below 0.2 nM, below 0.1 nM, below 0.09 nM, below 0.08 nM, below 0.07 nM, below 0.06 nM, below 0.05 nM, below 0.04 nM, below 0.03 nM, below 0.02 nM, below 0.01 nM, below 0.009 nM, below 0.008 nM, below 0.007 nM, below 0.006 nM, or below 0.005 nM, e.g. when assessed using the assay described in Example 2.
- the compound of the invention may comprise a residue ⁇ , i.e. a residue selected from Lys, Arg, Orn and Cys in which the side chain is conjugated to a lipohilic substituent.
- the substituent binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the compounds of the invention from enzymatic degradation and renal clearance and thereby enhancing the half-life of the compounds. It may also modulate the potency of the compound, e.g. with respect to the GIP receptor, the glucagon receptor and/or the GLP-1 receptor.
- plasma proteins e.g. albumin
- the substituent is conjugated to the functional group at the distal end of the side chain from the alpha-carbon.
- the normal ability of the Lys, Arg, Orn or Cys side chain to participate in interactions mediated by that functional group may therefore be reduced or completely eliminated by the presence of the substituent.
- the overall properties of the compound may be relatively insensitive to changes in the actual amino acid present as residue ⁇ . Consequently, it is believed that any of the residues Lys, Arg, Orn and Cys may be present at any position where ⁇ is permitted.
- it may be advantageous that the amino acid component of ⁇ is Lys.
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z 1 or —Z 2 —Z 1 .
- —Z 1 is a fatty chain having at a terminus a connection —X— to ⁇ or to Z 2 ;
- —X— is a bond, —CO—, —SO—, or —SO 2 —;
- Z 1 has a polar group at the end of the chain distal from connection —X—; said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;
- each Y is independently —NH, —NR, —S or —O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z 2 ;
- each X is independently a bond, CO—, SO—, or SO 2 —;
- each V is independently a bivalent organic moiety linking Y and X;
- n 1-10.
- Z 1 is a fatty chain having a connection to ⁇ or to Z 2 , referred to herein as —X—.
- —X— may be, for example, a bond, acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO 2 —).
- —X— is acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO 2 —).
- —X— is acyl (—CO—).
- Z 1 may further have a polar group, said polar group being located at the end of the chain distal from the connection —X—.
- the connection is located at the ⁇ -position with respect to the polar group.
- the polar group may be bound directly to the terminus of the fatty chain, or may be bound via a linker.
- the polar group is an acidic or weakly acid group, for example a carboxylic acid or a carboxylic acid bioisostere, a phosphonate, or a sulfonate.
- the polar group may have a pK a of between ⁇ 2 and 12 in water, more preferably between 1 and 7, more preferably between 3 and 6.
- Certain preferred polar groups have a pK a of between 4 and 5.
- the polar group may comprise a carboxylic acid (—COOH) or a carboxylic acid bioisostere, a phosphonic acid (—P(O)(OH) 2 ), or a sulfonic acid (—SO 2 OH) group.
- the polar group if present, comprises a carboxylic acid or carboxylic acid bioisostere.
- Suitable carboxylic acid bioisosteres are known in the art.
- the bioisostere has a proton having a pK a similar to the corresponding carboxylic acid.
- suitable bioisoteres may include, not by way of limitation, tetrazole, acylsulfomides, acylhydroxylamine, and squaric acid derivatives, as shown below (--- indicates the point of attachment):
- Fatty chain refers to a moiety comprising a chain of carbon atoms, the carbon atoms being predominantly substituted with hydrogen or hydrogen-like atoms, for example, a hydrocarbon chain.
- Such fatty chains are often referred to as lipophilic, although it will be appreciated that substitution may alter the lipophilic properties of the overall molecule.
- the fatty chain may by aliphatic. It may be entirely saturated or may include one or more double or triple bonds. Each double bond, if present, may be in the E or Z configuration.
- the fatty chain may also have one or more cycloalkylene or heterocycloalkylene moieties in its length, and additionally or alternatively may have one or more arylene or heteroarylene moieties in its length.
- the fatty chain may incorporate a phenylene or piperazinylene moiety in its length as, for example, shown below (wherein --- represents the points of attachment within the chain).
- the fatty chain may be derived from a fatty acid, for example, it may be derived from a medium-chain fatty acid (MCFA) with an aliphatic tail of 6-12 carbon atoms, a long-chain fatty acid (LCFA) with an aliphatic tail of 13-21 carbon atoms, or a very long-chain fatty acid (LCFA) with an aliphatic tail of 22 carbon atoms or more.
- MCFA medium-chain fatty acid
- LCFA long-chain fatty acid
- LCFA very long-chain fatty acid
- linear saturated fatty acids from which suitable fatty chains may be derived include tridecylic (tridecanoic) acid, myristic (tetradecanoic) acid, pentadecylic (pentadecanoic) acid, palmitic (hexadecanoic) acid, and margaric (heptadecanoic) acid.
- linear unsaturated fatty acids from which suitable fatty chains may be derived include myristoleic acid, palmitoleic acid, sapienic acid and oleic acid.
- the fatty chain may be connected to ⁇ or to Z 2 by an amide linkage, a sulfinamide linkage, a sulfonamide linkage, or by an ester linkage, or by an ether, thioether or amine linkage. Accordingly, the fatty chain may have, a bond to ⁇ or to Z 2 or an acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO 2 —) group.
- the fatty chain has a terminus having an acyl (—CO—) group and is connected to ⁇ or Z 2 by an amide or ester linkage.
- Z 1 is a group of formula:
- A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;
- B is a bond or a linker
- X is a bond, acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO 2 —);
- Alk is a fatty chain that may be optionally substituted with one or more substituents.
- the fatty chain is preferably 6 to 28 carbon atoms in length (e.g. a C 6-28 alkylene), more preferably, 12 to 26 carbons in length (e.g. a C 12-26 alkylene), more preferably, 16 to 22 carbons in length (e.g. C 16-22 alkylene), and may be saturated or unsaturated.
- Alk is saturated, that is, preferably Alk is alkylene.
- Optional substituents on the fatty chain may be independently selected from fluoro, C 1-4 alkyl, preferably methyl; trifluoromethyl, hydroxymethyl, amino, hydroxyl, C 1-4 alkoxy, preferably methoxy; oxo, and carboxyl, and may be independently located at any point along the chain.
- each optional substituent is selected from fluoro, methyl, and hydroxyl. Where more than one substituent is present, substituents may be the same or different.
- the number of substituents is 0 to 3; more preferably the fatty chain is unsubstituted.
- B may be a bond or a linker.
- B When B is a linker, it may be a cycloalkylene, heterocycloalkylene, C 6 arylene, or C 5-6 heteroarylene, or C 6 arylene-O— or C 5-6 heteroarylene-O—.
- B When B is phenylene it may, for example, be selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, preferably 1,4-phenylene (so that A-B— is a 4-benzoic acid substituent or 4-benzoic acid bioisostere).
- B When B is phenylene-O—, it may, for example, be selected from 1,2-phenylene-O—, 1,3-phenylene-O—, 1,4-phenylene-O—, preferably 1,4-phenylene-O.
- Each phenylene of B may be optionally substituted with one or more substituents selected from fluoro, methyl, trifluoromethyl, amino, hydroxyl, and C 1-4 alkoxy, preferably methoxy.
- B may be C 5-6 heteroarylene, for example, pyridinylene or thiofuranylene, and may be optionally substituted as described.
- A-B— may be selected from:
- A-B-Alk- is an alkyl chain of formula H 3 C—(CH 2 ) n —.
- Z 1 is an acyl group of formula:
- Z 1 is an acyl group of formula:
- A is —COOH and B is a bond.
- certain preferred Z 1 are derived from long-chain saturated ⁇ , ⁇ -dicarboxylic acids of formula HOOC—(CH 2 ) 12-22 —COOH, preferably, long-chain saturated ⁇ , ⁇ -dicarboxylic acids having an even number of carbon atoms in the aliphatic chain.
- A is H and B is a bond.
- certain preferred Z 1 are derived from long-chain saturated carboxylic acids of formula HOOC—(CH 2 ) 12-22 —CH 3 , preferably, long-chain saturated carboxylic acids having an even number of carbon atoms in the aliphatic chain.
- Z 1 may be:
- the carboxylic acid group if present, may be replaced by a bioisotere as detailed herein.
- Z 2 is an optional spacer that connects Z 1 to the side chain of the amino acid component of ⁇ .
- Z 2 if present, is a spacer bound at one terminus by Y, which may be a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which may be a bond or an acyl (—CO—), sulfinyl (—SO—), sulfonyl (—SO 2 —) or absent.
- Z 2 may be a spacer of formula (--- indicate points of attachment):
- Y may be —NH, —NR, —S or —O, where R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z 1 ;
- X may be a bond, CO—, SO—, or SO 2 —, with the remaining valency forming a linkage to the side chain of the amino acid component of Y;
- V is a bivalent organic moiety linking Y and X;
- n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Where n is 2 or more, each Y, V, and X is independent of every other Y, V, and X.
- Z 2 may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z 1 and the side chain.
- each V may also be bound to each adjacent V by linkages as described.
- linkages are amides, esters or sulfonamides, most preferably amides.
- each Y is —NH or —NR and each X is CO— or SO 2 —.
- —X— is acyl (—CO—).
- Z 2 is a spacer of formula —S A —, —S B —, —S A —S B — or —S B —S A —, wherein S A and S B are as defined below.
- Z 2 is selected from —S A — or —S B —S A —, that is, [side chain]—Z 2
- Z 1 is [side chain]—S A —Z 1 or [side chain]—S B —S A —Z 1 .
- S A may be a single amino acid residue or a residue of an amino acid derivative, especially an amino acid derivative residue having a sulfinyl or sulfonyl in place of the carboxy moiety at the C terminus. Additionally or alternatively, the single amino acid residue may have an oxygen or sulfur atom in place of the nitrogen atom at the N terminus.
- S A is a single amino acid residue.
- the amino acid may be selected from ⁇ -Glu, ⁇ -Glu, ⁇ -Asp, ⁇ -Asp, Ala, ⁇ -Ala (3-aminopropanoic acid), Dapa (2,3-diaminopropanoic acid), Dab (2,4-diaminobutanoic acid), and Gaba (4-aminobutanoic acid).
- connection may be at any moiety as appropropriate. Any carboxylic acid or amino resides not bound within the residue may be free, that is, present as a free carboxylic acid or primary amine, or may be derivatised. Suitable derivatisation is known in the art.
- carboxylic acid moieties may be present in S A amino acid residues as esters, for example, as methyl esters.
- Amino moieties may be present as alkylated amines, for example, methylated, or may be protected as amide or carbamate moieties.
- Other suitable amino acids include ⁇ -Ala (3-aminopropanoic acid) and Gaba (4-aminobutanoic acid) and similar w amino acids.
- amino acids may be D or L, or a racemic or enantioenriched mixture.
- the amino acid is an L-amino acid.
- the amino acid is a D-amino acid.
- S A has a carboxylic acid substituent, with ⁇ -Glu, ⁇ -Glu, ⁇ -Asp, and ⁇ -Asp, and sulfinyl and sulfonyl derivatives thereof, being preferred. Accordingly, in some embodiments, the amino acid residue is:
- —X— is —CO—, —SO—, —SO 2 —, preferably —CO—, and a is 1 or 2, preferably 2.
- the carboxylic acid is an ester, and the amino acid residue is:
- —X— is —CO—, —SO—, —SO 2 —, preferably —CO—, and a is 1 or 2, preferably 2, and R is C 1-4 alkyl or C 6 aryl.
- R is C 1-4 alkyl, preferably methyl or ethyl, more preferably ethyl.
- a preferred S A group bearing a carboxylic acid is ⁇ -Glu.
- S A is selected from Dapa or ⁇ -Glu. Most preferably, S A is ⁇ -Glu.
- S B may be a linker of general formula:
- each polymeric unit P U may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z 1 , S A , and Lys.
- each P U may be independently a unit of formula:
- Y may be —NH, —NR, —S or —O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z 1 ;
- X may be a bond, CO—, SO—, or SO 2 —, with the remaining valency forming a linkage to the ⁇ side chain;
- V is a bivalent organic moiety linking Y and X.
- V is the ⁇ -carbon of a natural or unnatural amino acid, that is V is —CHR AA —, wherein R AA is an amino acid side chain; or V is an optionally substituted C 1-6 alkylene, or V is a chain comprising one or more units of ethylene glycol in series, also known as PEG chain, for example, —CH 2 CH 2 —(OCH 2 CH 2 ) m —O—(CH 2 ) p —, where m is 0, 1, 2, 3, 4, or 5, and p is 1, 2, 3, 4, or 5; when X is CO—, p is preferably 1, 3, 4, or 5.
- Optional alkylene substituents include fluoro, methyl, hydroxy, hydroxymethy, and amino.
- Preferred P U units include:
- S B may comprise one or more of each of P U i , P U ii , and P U ii in any order, or may comprise one or more units of P U i , P U ii , and P U i only, or one of more units selected from P U i and P U ii , P U i and P U iii , or P U ii and P U iii .
- Each P U i may be independently selected from any natural or unnatural amino acid residue and, for example, may be selected from Gly, Pro, Ala, Val, Leu, lie, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, ⁇ -Glu, ⁇ -Glu, Asp, Ser Thr, Dapa, Gaba, Aib, ⁇ -Ala, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, and 10-aminodecanoyl.
- P U i amino acid residues are selected from Gly, Ser, Ala, Thr, and Cys, more preferably from Gly and Ser.
- S B is —(P U i ) n —, wherein n is 1 to 8, more preferably 5 to 7, most preferably 6. In some preferred embodiments, S B is —(P U i ) n —, n is 6 and each P U i is independently selected from Gly or Ser, with a preferred sequence being -Gly-Ser-Gly-Ser-Gly-Gly- (SEQ ID NO: 114).
- P U ii dipeptide residues Each P U i may be independently selected from any dipeptide residue comprising two natural or unnatural amino acid residues bound by an amide linkage.
- Preferred P U ii dipeptide residues include Gly-Gly, Gly-Ser, Ser-Gly, Gly-Ala, Ala-Gly, and Ala-Ala, more preferably Gly-Ser and Gly-Gly.
- S B is —(P U ii ) n —, wherein n is 2 to 4, more preferably 3, and each P U ii is independently selected from Gly-Ser and Gly-Gly.
- S B is —(P U ii ) n —, n is 3 and each P U i is independently selected from Gly-Ser and Gly-Gly, with a preferred sequence being -(Gly-Ser)-(Gly-Ser)-(Gly-Gly) (SEQ ID NO: 114).
- Amino acids having stereogenic centres within P U i and P U ii may be racemic, enantioenriched, or enantiopure.
- the or each amino acid is independently an L-amino acid.
- the or each amino acid is independently a D-amino acid.
- Each P U iii may be independently a residue of general formula:
- m is 0, 1, 2, 3, 4, or 5, preferably 1 or 2
- p is 1, 3, 4, or 5, preferably 1.
- m is 1 and p is 1, that is, P U iii is a residue of 8-amino-3,6-dioxaoctanoic acid (also known as ⁇ 2-[2-aminoethoxy]ethoxy ⁇ acetic acid and H 2 N-PEG 3 -COOH). This residue is referred to herein as -PEG 3 -.
- PEG chains are also known in the art.
- 11-amino-3,6,9-trioxaundecanoic acid also known as H 2 N-PEG 4 -COOH or -PEG 4 -.
- S B is —(P U iii ) n —, wherein n is 1 to 3, more preferably 2.
- S B is -PEG 3 -PEG 3 -.
- the compounds of the invention may provide an attractive treatment option for metabolic diseases including obesity and diabetes mellitus (diabetes).
- Diabetes comprises a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Acute signs of diabetes include excessive urine production, resulting compensatory thirst and increased fluid intake, blurred vision, unexplained weight loss, lethargy, and changes in energy metabolism. However, symptoms are often not severe or may be absent.
- the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart and blood vessels. Diabetes is classified into type 1 diabetes, type 2 diabetes and gestational diabetes on the basis on pathogenetic characteristics. Type 1 diabetes accounts for 5-10% of all diabetes cases and is caused by auto-immune destruction of insulin-secreting pancreatic ⁇ -cells.
- Type 2 diabetes accounts for 90-95% of diabetes cases and is a result of a complex set of metabolic disorders. However, symptoms are often not severe or may be absent. Type 2 diabetes is the consequence of endogenous insulin production becoming insufficient to maintain plasma glucose levels below diagnostic thresholds.
- Gestational diabetes refers to any degree of glucose intolerance identified during pregnancy.
- Pre-diabetes includes impaired fasting glucose and impaired glucose tolerance and refers to those states that occur when blood glucose levels are elevated but below the levels that are established for the clinical diagnosis for diabetes.
- a large proportion of people with type 2 diabetes and pre-diabetes are at increased risk of morbidity and mortality due to the high prevalence of additional metabolic risk factors, including abdominal obesity (excessive fat tissue around the abdominal internal organs), atherogenic dyslipidemia (blood fat disorders including high triglycerides, low HDL cholesterol and/or high LDL cholesterol, which foster plaque buildup in artery walls), elevated blood pressure (hypertension) a prothrombotic state (e.g. high fibrinogen or plasminogen activator inhibitor- 1 in the blood), and/or a proinflammatory state (e.g., elevated C-reactive protein in the blood).
- abdominal obesity excessive fat tissue around the abdominal internal organs
- atherogenic dyslipidemia blood fat disorders including high triglycerides, low HDL cholesterol and/or high LDL cholesterol, which foster plaque buildup in artery walls
- elevated blood pressure hypertension
- a prothrombotic state e.g. high fibrinogen or plasminogen activator inhibitor- 1 in the blood
- obesity confers an increased risk of developing pre-diabetes, type 2 diabetes as well as, e.g., certain types of cancer, obstructive sleep apnea and gall-bladder disease.
- Dyslipidemia is associated with increased risk of cardiovascular disease.
- High Density Lipoprotein (HDL) is of clinical importance since an inverse correlation exists between plasma HDL concentrations and risk of atherosclerotic disease.
- the majority of cholesterol stored in atherosclerotic plaques originates from LDL and hence an elevated concentration of Low Density Lipoproteins (LDL) is closely associated with atherosclerosis.
- LDL Low Density Lipoproteins
- the HDL/LDL ratio is a clinical risk indictor for atherosclerosis and coronary atherosclerosis in particular.
- glucagon-GIP-GLP1 triple agonists act as glucagon-GIP-GLP1 triple agonists.
- the triple agonist may combine the effect of glucagon, e.g., on fat metabolism with the effect of GIP on improved glycemic control and the effect of GLP-1 e.g., on blood glucose levels and food intake. They may therefore act to accelerate elimination of excessive adipose tissue, induce sustainable weight loss, and improve glycemic control.
- Triple glucagon-GIP-GLP1 agonists may also act to reduce cardiovascular risk factors such as high cholesterol and such as high LDL-cholesterol.
- the triple agonist compounds of the present invention may therefore be used (alone or in combination) as pharmaceutical agents for preventing weight gain, promoting weight loss, reducing excess body weight or treating obesity (e.g., by control of appetite, feeding, food intake, calorie intake, and/or energy expenditure and lipolysis), including morbid obesity, as well as associated diseases and health conditions including but not limited to obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.
- the compounds may also be used for treatment of insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, dyslipidemia (or a combination of these metabolic risk factors), atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke. These are all conditions which may be associated with obesity. However, the effects of the compounds employed in the context of the invention on these conditions may be mediated in whole or in part via an effect on body weight, or may be independent thereof.
- the triple agonist compounds may thus be used (alone or in combination) for the treatment and/or prevention of any of the diseases, disorders, or conditions described herein, including insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof.
- the diabetes related disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and proinflammatory state, or a combination thereof.
- the blood fat disorder is selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof.
- the prothrombotic state is selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood.
- the proinflammatory state is an elevated C-reactive protein level in the blood.
- the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.
- the triple agonist compounds may also be used for the treatment and/or prevention of any of the diseases, disorders, or conditions associated with diabetes related osteoporosis including increased risk of bone fractures.
- the observed increase in fracture risk is likely to be related to impaired bone quality rather than to bone mineral density.
- the related mechanisms due at least in part to hyperglycemia, neuropathy, and higher incidence of hypovitaminosis D, are not yet fully understood.
- the invention provides the use of a triple agonist compound as described, in the manufacture of a medicament for any of the clinical applications described in this specification. Reference to a compound for use in any such method should be construed accordingly.
- the invention also provides a therapeutic kit comprising a triple agonist of the invention, optionally in combination with a pharmaceutically acceptable carrier.
- the invention provides a device comprising a triple agonist of the invention for delivery of the triple agonist to a subject.
- the triple agonist compounds of the present invention, or salts or solvates thereof may be formulated as pharmaceutical compositions prepared for storage or administration, which typically comprise a therapeutically effective amount of a compound employed in the context of the invention, or a salt or solvate thereof, in a pharmaceutically acceptable carrier.
- the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of the triple agonist compound
- the therapeutically effective amount of a compound of the present invention will depend, e.g., on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts. The dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials.
- An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person.
- pharmaceutically acceptable carrier includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, sterile saline and phosphate- buffered saline at slightly acidic or physiological pH may be used.
- Suitable pH buffering agents may be, e.g., phosphate, citrate, acetate, lactate, maleate, tris/hydroxymethyl)aminomethane (TRIS), N-Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
- TIS tris/hydroxymethyl)aminomethane
- TAPS N-Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid
- ammonium bicarbonate diethanolamine
- histidine which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
- the term further encompasses any agents listed in the US Pharmacopeia for use in animals, including humans.
- salts include pharmaceutically acceptable salts, such as, e.g., acid addition salts and basic salts.
- acid addition salts include hydrochloride salts, citrate salts and acetate salts.
- basic salts include salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals such as calcium, and ammonium ions + N(R 3 ) 3 (R 4 ), where R 3 and R 4 independently designate optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
- Treatment is an approach for obtaining beneficial or desired clinical results.
- beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment may also mean prolonging survival as compared to expected survival if not receiving treatment.
- Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. Accordingly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures in certain embodiments.
- Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.
- treatment is meant inhibiting or reducing an increase in pathology or symptoms (e.g. weight gain, hyperglycemia) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition.
- compositions of the invention may be in unit dosage form.
- the composition is divided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. It may be provided in single dose injectable form, for example in the form of an injection pen.
- Compositions may be formulated for any suitable route and means of administration.
- Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Subcutaneous or transdermal modes of administration may be particularly suitable for certain of the compounds described herein.
- a compound of the invention may be administered as part of a combination therapy with at least one other agent for treatment of diabetes, obesity, dyslipidemia, or hypertension.
- the at least two active agents may be given together or separately, and as part of the same pharmaceutical formulation or as separate formulations.
- the triple agonist compound (or the salt or solvate thereof) may be used in combination with an antidiabetic agent including but not limited to metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, or insulin.
- the compound or salt or solvate thereof is used in combination with insulin, DPP-IV inhibitor, sulfonylurea or metformin, particularly sulfonylurea or metformin, for achieving adequate glycemic control.
- the compound or salt or solvate thereof is used in combination with insulin or an insulin analogue for achieving adequate glycemic control.
- insulin analogues include but are not limited to LANTUS®, NOVORAPID®, HUMALOG®, NOVOMIX®, ACTRAPHANE HM®, LEVEMIR® and APIDRA®.
- the triple agonist compound or salt or solvate thereof may further be used in combination with one or more of an anti-obesity agent, including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist.
- an anti-obesity agent including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist.
- the triple agonist compound or salt or solvate thereof may be used in combination with an anti-hypertension agent, including but not limited to an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretics, beta-blocker, or calcium channel blocker.
- an anti-hypertension agent including but not limited to an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretics, beta-blocker, or calcium channel blocker.
- the triple agonist compound or salt thereof may be used in combination with an anti-dyslipidemia agent, including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.
- an anti-dyslipidemia agent including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.
- the invention provides a nucleic acid encoding a peptide having the sequence X1-X30 of Formula I. Also provided is an expression construct (also known as an expression vector) comprising a nucleic acid of the invention in operable linkage with suitable regulatory elements to direct expression of the peptide, e.g. transcription and translation.
- an expression construct also known as an expression vector
- the invention also provides a host cell comprising a nucleic acid or expression construct and capable of expressing, and optionally secreting, the peptide.
- the invention provides a method of producing a compound of the invention, the method comprising culturing the host cells described above under conditions suitable for expressing the compound and purifying the compound thus produced.
- the invention also provides a nucleic acid molecule, an expression vector, or a host cell, as described above, for use in a method of medica treatment, and in particular for treatment of the metabolic disorders discussed elsewhere in this specification.
- a nucleic acid molecule may encode a compound of the invention, a peptide having the amino acid sequence X1-X30 of Formula I, or a peptide which is a precursor of a compound of the invention.
- nucleic acid sequences will be provided as expression constructs wherein the encoding nucleic acid is in functional linkage with appropriate control sequences to direct its expression.
- the invention provides a method of producing a triple agonist of the invention, the method comprising expressing an amino acid precursor of the triple agonist and modifying the precursor to provide the triple agonist.
- the modification may comprise chemical modification of a Lys, Arg or Cys residue present at a position ⁇ to introduce the lipophilic moiety, modification of the N- or C-terminus, and/or modification of any other amino acid side chains in the molecule (e.g. to introduce a non-naturally occurring amino acid residue).
- the compounds of the invention may also be manufactured by standard peptide synthetic methods, e.g. by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and isolating and purifying the final peptide compound product, or by any combinations of recombinant and synthetic methods.
- Piperidine/NMP (20%; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40° C.). The reaction vessel was drained and a second portion of piperidine/DMF (20%; 10 ml) was added and heated (75° C.; 3 min.) again. The resin was then washed with NMP (6 ⁇ 10 ml).
- Fmoc-Lys(ivDde)-OH or alternatively another amino acid with an orthogonal side chain protective group was introduced at the position of the acylation.
- the N-terminal of the peptide backbone was then Boc-protected using Boc2O or alternatively by using a Boc-protected amino acid in the last coupling. While the peptide was still attached to the resin, the orthogonal side chain protective group was selectively cleaved using freshly prepared hydrazine hydrate (2-4%) in NMP for 2 ⁇ 15 min.
- the unprotected lysine side chain was first coupled with Fmoc-Glu-OtBu or another spacer amino acid, which was deprotected with piperidine and acylated with a lipophilic moiety using the peptide coupling methodology as described above.
- Abbreviations employed are as follows:
- COMU 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholinomethylene)]methanaminium hexafluorophosphate
- ivDde 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl
- DIPEA diisopropylethylamine
- TIS triisopropylsilane
- the resin was washed with EtOH (3 ⁇ 10 ml) and Et 2 O (3 ⁇ 10 ml) and dried to constant weight at room temperature (r.t.).
- the crude peptide was cleaved from the resin by treatment with TFA/TIS/water (95/2.5/2.5; 40 ml, 2 h; r.t.). Most of the TFA was removed at reduced pressure and the crude peptide was precipitated and washed three times with diethylether and dried to constant weight at room temperature.
- the crude peptide was purified to greater than 90% by preparative reverse phase HPLC using a PerSeptive Biosystems VISION Workstation equipped with a C-18 column (5 cm; 10 ⁇ m) and a fraction collector and run at 35 ml/min with a gradient of buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.). Fractions were analyzed by analytical HPLC and MS and relevant fractions were pooled and lyophilized. The final product was characterized by HPLC and MS. The synthesized compounds are shown in Table 1:
- H-YSQGTFTSDYSKYLDSKAAHDFVEWLLRA-NH 2 (SEQ ID NO: 1) 2 H-Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSA-NH 2 (SEQ ID NO: 2) 3 H-Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA-NH 2 (SEQ ID NO: 3) 4 H-YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-KAAHDFVEWLLRA- NH 2 (SEQ ID NO: 4) 5 H-Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA-NH 2 (SEQ ID NO: 5) 6 H-Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA-NH 2 (SEQ ID NO: 6) 7 H-Y-A
- GIP-R Human GIP Receptor
- GLP-1-R GLP-1 Receptor
- GCG-R Glucagon Receptor
- HEK293 cells expressing the human GIP R, GLP-1 R or GCG R (stable cell lines generated through transfection of the cDNA for human GIP R, GLP-1 R or GCG R and selection of stable clones) were seeded at 30,000 cells/well in 96-well microtiter plates coated with 0.01% poly-L-lysine, and grown for 1 day in culture in 200 ⁇ l growth medium (DMEM, 10% FCS, Penicillin (100 IU/ml), Streptomycin (100 ⁇ g/ml)).
- DMEM 10% FCS
- Penicillin 100 IU/ml
- Streptomycin 100 ⁇ g/ml
- Results were converted into cAMP concentrations using a cAMP standard curve prepared in KRBH buffer containing 0.1% (v/v) DMSO. The resulting cAMP curves were plotted as absolute cAMP concentrations (nM) over log (test compound concentration) and analyzed using the curve fitting program XLfit.
- the exemplified compounds of the invention will have activities at the GCG-R that are close to that of native glucagon. At the same time, it is anticipated that they will exhibit strong GLP-1-R activation with EC 50 well below 1 nM. Likewise, it is anticipated that these peptides will also exhibit strong GIP-R activity with and EC 50 below or just above 1 nM.
- mice Males with a body weight of approximately 25 g were given a single intravenous (i.v.) bolus of each peptide to be tested.
- blood samples were drawn 0.08, 0.17, 0.5, 1, 4, 8, 16 and 24 hours post-dose. Blood samples were drawn by sublingual bleeding.
- the dosing vehicle was a phosphate buffer containing mannitol (pH 7.5).
- mice were drawn, i.e. 16 mice were included for each compound.
- the mice were euthanized immediately after blood sampling by cervical dislocation.
- Plasma samples were analyzed after solid phase extraction (SPE) or precipitation by liquid chromatography mass spectrometry (LC-MS/MS). Mean plasma concentrations were used for calculation of the pharmacokinetic parameters using the non-compartmental approach in Phoenix WinNonlin 6.3.
- Plasma terminal elimination half-life (T1 ⁇ 2) was determined as In(2)/ ⁇ z where ⁇ z is the magnitude of the slope of the log linear regression of the log concentration versus time profile during the terminal phase. The results are summarized in Table 3
Abstract
Description
- The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jul. 29, 2021 is named 50412-096003_Sequence_Listing_07_29_21_ST25 and is 73,649 bytes in size.
- The invention relates to compounds having agonist activity at the glucagon, GIP and GLP-1 receptors, and to their use in the treatment of metabolic disorders.
- Diabetes and obesity are increasing health problems globally and are associated with various other diseases, particularly cardiovascular diseases (CVD), obstructive sleep apnea, stroke, peripheral artery disease, microvascular complications and osteoarthritis. There are 246 million people worldwide with diabetes, and by 2025 it is estimated that 380 million will have diabetes. Many have additional cardiovascular risk factors including high/aberrant LDL and triglycerides and low HDL. Cardiovascular disease accounts for about 50% of the mortality in people with diabetes, and the morbidity and mortality rates relating to obesity and diabetes underscore the medical need for efficacious treatment options.
- Pre-proglucagon is a 158 amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP-1 or GLP1), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM), which are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake. Glucagon is a 29-amino acid peptide that corresponds to amino acids 33 through 61 of pre-proglucagon, while GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of pre-proglucagon.
- When blood glucose begins to fall, glucagon, a hormone produced by the pancreas, signals the liver to break down glycogen and release glucose, causing blood glucose levels to rise toward a normal level. In addition to controlling glucose homeostasis, glucagon reduces body weight probably through inhibition of food intake and stimulation of energy expenditure and/or lipolysis. GLP-1 has different biological activities compared to glucagon. Its actions include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. GLP-1 has been shown to reduce hyperglycemia (elevated glucose levels) in diabetic patients.
- Exendin-4, a peptide from lizard venom that shares about 50% amino acid identity with GLP-1, activates the GLP-1 receptor and likewise has been shown to reduce hyperglycemia in diabetic patients.
- Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that, like GLP-1, stimulates insulin secretion from pancreatic β(beta) cells in the presence of elevated blood glucose levels. It is derived by proteolytic processing from a 133-amino acid precursor, preproGlP.
- Interestingly, novel glucagon-GLP-1 dual acting receptor agonists are currently in pre-clinical development (see, e.g., WO2011/006497). In comparison to GLP-1 analogues, glucagon-GLP-1 dual agonists are associated with more profound and sustained body weight loss in animal models on top of the improvements in glycemic control. Thus, glucagon based drugs may have promise for the treatment of type 2 diabetes mellitus and/or obesity.
- Incretins are gastrointestinal hormones that regulate blood glucose by enhancing glucose-stimulated insulin secretion (Drucker, D J and Nauck, M A, Lancet 368: 1696-705 (2006)). Two of the above mentioned peptides are known as incretins: GLP-1 and GIP. The discovery of the incretins has led to the development of two new classes of drugs for the treatment of diabetes mellitus. Thus, injectable GLP-1 receptor agonists, and small molecule compounds (oral DPP-4 inhibitors) that inhibit enzymatic inactivation of both endogenous GLP-1 and GIP, are now on the market (GLP-1 receptor agonists: Byetta™, Bydureon™ Lixisenatide™ and Liraglutide™, and DPP-4 inhibitors: Januvia™ Galvus™ Onglyza™ and Trajenta™). Apart from the acute effects of GLP-1 and GIP on insulin secretion, the two peptides also have long term effects. Evidence from several labs indicates that GLP-1 R agonists protect pancreatic β-cells by inhibiting apoptosis and enhancing proliferation. For instance, the study by Farilla et al. showed that GLP-1 had anti-apoptotic effects in human islets (Farilla, L, Endocrinology 144: 5149-58 (2003)). Such effects have not been reported for GIP until recently. In 2010, Weidenmaier et al. reported that a DPP-4 resistant GIP analogue has anti-apoptotic effects (Weidenmaier, S D, PLOS One 5(3): e9590 (2010)). Interestingly, in a mice model of diabetes and obesity the combination of the GLP-1 receptor agonist Liraglutide and an acylated GIP analogue show superior effects compared to treatment with Liraglutide or GIP analogue alone (Gault, V A, Clinical Science 121: 107-117 (2011)).
- Chronic treatment with the GLP-1 receptor agonists causes significant weight loss in diabetic humans. Interestingly, extended use of DPP-4 inhibitors in similar patients does not consistently change body weight. Evidence suggests (Matthias Tschöp oral presentation at ADA (American Diabetes Association), 2011) that body weight loss associated with GLP-1 agonist treatment is enhanced when GLP-1 and GIP are co-administered. In rodents, co-administration of GLP-1 and GIP results in greater body weight loss than GLP-1 treatment alone (Finan, Sci Transl Med. 2013; 5(209):209ra151. Irwin N et al, 2009, Regul Pept; 153: 70-76. Gault et al, 2011, Clin Sci; 121:107-117). Thus, in addition to improving blood glucose, GIP may also enhance GLP-1-mediated body weight loss. In the same presentation it was also shown that combining glucagon, GLP-1 and GIP receptor agonism led to further body weight loss in DIO mice.
- By combining glucagon, GLP-1 and GIP receptor agonism in novel inventive peptides it is anticipated that superior glycemic control and body weight loss can be achieved. Such peptides are likely to have strong incretin actions and improved β-cell preservation from the GLP-1 and GIP components, and have improved body weight loss from all three components by stimulating energy expenditure, lipolysis and reducing food intake.
- Broadly, the present invention concerns Glucagon-GLP-1-GIP triple agonists (referred to in this specification as “triple agonists”) which comprise one or more substitutions as compared to wild-type glucagon and which may have the property of an altered, preferably increased GIP and GLP-1 receptor activity, e.g. as assessed in in vitro efficacy assays. In the present invention it has been found that Glucagon-GLP-1-GIP triple acting receptor agonists are superior to existing and marketed GLP-1 analogues because the triple agonists offer improved glycemic control, possible islet and β-cell preservation and enhanced body weight loss. The Glucagon-GLP-1-GIP triple agonists could be used as therapeutics for both type 2 diabetes mellitus, obesity and related disorders.
- The invention provides a triple agonist having the general formula I:
-
(I) (SEQ ID NO: 52) R1-Tyr-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12- X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24- Trp-Leu-X27-X28-X29-X30-Y1-R2 - wherein
- R1 is H— (i.e., hydrogen), C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
- X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;
- X10 is Tyr or Leu;
- X12 is Lys, Ile or ψ;
- X13 is Ala, Tyr or Aib;
- X15 is Asp or Glu;
- X16 is Ser, Glu, Lys or ψ;
- X17 is Lys or ψ
- X19 is Gln or Ala;
- X20 is Lys, His, Arg or ψ;
- X21 is Ala, Asp or Glu;
- X23 is Val or Ile;
- X24 is Asn, Glu or ψ;
- X27 is Leu, Glu or Val;
- X28 is Ala, Ser, Arg or ψ;
- X29 is Aib, Ala, Gln or Lys;
- X30 is Lys, Gly, or is absent;
-
Y1 is (SEQ ID NO: 53) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, (SEQ ID NO: 54) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, (SEQ ID NO: 55) Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, (SEQ ID NO: 56) Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, (SEQ ID NO: 57) Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser or (SEQ ID NO: 58) Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, or is absent; - ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent;
- and
- R2 is —NH2 or —OH;
- or a pharmaceutically acceptable salt or solvate thereof.
- In some embodiments, ψ is present at one of positions X12, X16 and X17.
- In some embodiments, the compound contains only one residue ψ, which may be present at any one of positions X12, X16, X17, X20, X24 or X28. For example, it may be present at one of X12, X16 and X17.
- In some embodiments, the compound may possess one or more of the following sets of residues:
- K12 and Y13; I12 and Y13; K12 and A13; I12 and A13; or ψ12 and Y13;
- D15 and S16; D15 and E16; E15 and K16; D15 and ψ16; E15 and S16; or E15 and ψ16;
- A19, H20, and D21; A19, K20, and D21; A19, R20, and D21; Q19, K20, and E21; A19, K20, and E21; or Q19, R20, and A21; but especially A19, H20, and D21; A19, R20, and D21 or Q19, R20, and A21;
- I23 and E24; V23 and E24; or V23 and N24;
- L27, R28, and A29; L27, S28, and A29; L27, A28, and Q29; E27, S28, and A29; or V27, and A28, and Aib29;
- E15 and K17;
- E15 and ψ17;
- E15 and ψ17 and Q19;
- Q19 and E24;
- E16 and ψ17 and Q19; and/or
- K16 and ψ17 and Q19.
- Any one of these sets of residues, or combinations thereof, may be combined with:
- Aib2, Ser2 or Ac4c2, especially Aib2; and/or
- Tyr10 or Leu10, especially Tyr10.
- Positions 1 to 29 may have the sequence
-
(SEQ ID NO: 1) YSQGTFTSDYSKYLDSKAAHDFVEWLLRA; (SEQ ID NO: 59) YSQGTFTSDSKYLDΨKAAHDFVEWLLRA; (SEQ ID NO: 5) Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA; (SEQ ID NO: 9) Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA; (SEQ ID NO: 14) Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA; (SEQ ID NO: 17) Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA; (SEQ ID NO: 18) Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA; (SEQ ID NO: 60) Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; (SEQ ID NO: 61) Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLSA; (SEQ ID NO: 62) Y-Aib-QGTFTSDYSKYLDSΨAAHDFVEWLLSA; (SEQ ID NO: 7) Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA; (SEQ ID NO: 8) Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA; (SEQ ID NO: 10) Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA; (SEQ ID NO: 16) Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA; (SEQ ID NO: 6) Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA; (SEQ ID NO: 15) Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA; (SEQ ID NO: 21) Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA; (SEQ ID NO: 19) Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA; (SEQ ID NO: 20) Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA; (SEQ ID NO: 63) Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSA; (SEQ ID NO: 64) Y-Aib-QGTFTSDYSIYLEΨKAAKEFVEWLLSA; (SEQ ID NO: 65) Y-Aib-QGTFTSDYSΨYLEKKAAKEFVEWLLSA; (SEQ ID NO: 11) Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA; (SEQ ID NO: 110) Y-Aib-QGTFTSDLSIALEKΨAQRAFVEWLLAQ; (SEQ ID NO: 67) Y-Aib-QGTFTSDYSKYLDEΨAAKDFIEWLESA; (SEQ ID NO: 68) Y-Aib-QGTFTSDYSIYLDEΨAAKDFVEWLESA; (SEQ ID NO: 69) Y-Aib-QGTFTSDYSIYLDEΨAAKDFIEWLESA; (SEQ ID NO: 70) Y-Aib-QGTFTSDYSIYLDEΨAAKEFIEWLESA; (SEQ ID NO: 3) Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA; (SEQ ID NO: 12) Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA; (SEQ ID NO: 71) Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLRA; (SEQ ID NO: 72) Y-Aib-QGTFTSDYSIYLEKΨAQRAFVEWLLRA; (SEQ ID NO: 73) Y-Aib-QGTFTSDYSIALDKΨAQRAFVNWLVA-Aib; (SEQ ID NO: 74) Y-Ac4c-QGTFTSDYSIYLDEΨAAKEFIEWLESA; (SEQ ID NO: 75) Y-Ac4c-QGTFTSDYSIALEKΨAQRAFVEWLLAQ; or (SEQ ID NO: 76) Y-Ac4c-QGTFTSDYSIYLDKΨAQRAFVEWLLAQ. - Alternatively, positions 1 to 29 may differ at up to 4 positions, e.g. at 1, 2, 3 or 4 positions, from any of the specific sequences shown above, within the constraints of Formula I.
- For example, positions 1 to 29 may differ at up to 4 positions, e.g. at 1, 2, 3 or 4 positions from one of the following sequences:
-
(SEQ ID NO: 63) Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSA; (SEQ ID NO: 60) Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; or (SEQ ID NO: 77) Y-Aib-QGTFTSDYSIALEKΨAQRAFVEWLLAQ. - Positions 1 to 29 may have the sequence:
-
(SEQ ID NO: 4) YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-KAAHDFVEWLLRA; (SEQ ID NO: 27) Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA; (SEQ ID NO: 85) Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA; (SEQ ID NO: 2) Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA; (SEQ ID NO: 22) Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-AAKEFVEWLLSA; (SEQ ID NO: 23) Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)-KAAKEFVEWLLSA; (SEQ ID NO: 24) Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)-YLEKKAAKEFVEWLLSA; (SEQ ID NO: 22) Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-AAKEFVEWLLSA; (SEQ ID NO: 86) Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AAKEFVEWLLSA; (SEQ ID NO: 87) Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)- AAKEFVEWLLSA; (SEQ ID NO: 88) Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQ; (SEQ ID NO: 89) Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-isoGlu)- AQRAFVEWLLAQ; (SEQ ID NO: 90) Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; (SEQ ID NO: 91) Y-Aib-QGTFTSDYSIYLD-K(eicosanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; (SEQ ID NO: 92) Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQ; (SEQ ID NO: 93) Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; (SEQ ID NO: 94) Y-Aib-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQ; (SEQ ID NO: 95) Y-Aib-QGTFTSDLSIALE-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; (SEQ ID NO: 25) Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA; (SEQ ID NO: 29) Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLESA; (SEQ ID NO: 30) Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA; (SEQ ID NO: 38) Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AAKEFIEWLESA; (SEQ ID NO: 39) Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)- AAKEFIEWLESA; (SEQ ID NO: 26) Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA; (SEQ ID NO: 96) Y-Aib-QGTFTSDYSIYLE-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVEWLLRA; (SEQ ID NO: 97) Y-Aib-QGTFTSDYSIYLE-K([17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLRA; (SEQ ID NO: 98) Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib; (SEQ ID NO: 99) Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-Dapa-Peg3-Peg3)-AQRAFVNWLVA-Aib; (SEQ ID NO: 100) Y-Aib-QGTFTSDYSIALDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVNWLVA-Aib; (SEQ ID NO: 40) Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAKEFIEWLESA; (SEQ ID NO: 101) Y-Ac4c-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQ; or (SEQ ID NO: 102) Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQ. - The peptide backbone of Formula I may have the sequence:
-
(SEQ ID NO: 1) YSQGTFTSDYSKYLDSKAAHDFVEWLLRA; (SEQ ID NO: 59) YSQGTFTSDYSKYLDΨKAAHDFVEWLLRA; (SEQ ID NO: 5) Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA; (SEQ ID NO: 9) Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA; (SEQ ID NO: 13) Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 14) Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA; (SEQ ID NO: 17) Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA; (SEQ ID NO: 18) Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA; (SEQ ID NO: 60) Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; (SEQ ID NO: 78) Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 62) Y-Aib-QGTFTSDYSKYLDSΨAAHDFVEWLLSA; (SEQ ID NO: 7) Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA; (SEQ ID NO: 8) Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA; (SEQ ID NO: 10) Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA; (SEQ ID NO: 16) Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA; (SEQ ID NO: 6) Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA; (SEQ ID NO: 15) Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA; (SEQ ID NO: 21) Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA; (SEQ ID NO: 19) Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA; (SEQ ID NO: 20) Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA; (SEQ ID NO: 63) Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSA; (SEQ ID NO: 64) Y-Aib-QGTFTSDYSIYLEΨKAAKEFVEWLLSA; (SEQ ID NO: 65) Y-Aib-QGTFTSDYSΨYLEKKAAKEFVEWLLSA; (SEQ ID NO: 79) Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 11) Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA; (SEQ ID NO: 80) Y-Aib-QGTFTSDYSIYLDKΨAQRAFVEWLLAQGPSSGAPPPS; (SEQ ID NO: 81) Y-Aib-QGTFTSDYSIALEKΨAQRAFVEWLLAQK; (SEQ ID NO: 66) Y-Aib-QGTFTSDLSIALEKΨAQRAFVEWLLAQK; (SEQ ID NO: 67) Y-Aib-QGTFTSDYSKYLDEΨAAKDFIEWLESA; (SEQ ID NO: 68) Y-Aib-QGTFTSDYSIYLDEΨAAKDFVEWLESA; (SEQ ID NO: 69) Y-Aib-QGTFTSDYSIYLDEΨAAKDFIEWLESA; (SEQ ID NO: 70) Y-Aib-QGTFTSDYSIYLDEΨAAKEFIEWLESA; (SEQ ID NO: 3) Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA; (SEQ ID NO: 12) Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA; (SEQ ID NO: 71) Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLRA; (SEQ ID NO: 72) Y-Aib-QGTFTSDYSIYLEKΨAQRAFVEWLLRA; (SEQ ID NO: 82) Y-Aib-QGTFTSDYSIALDKΨAQRAFVNWLVA-Aib-KPSSGAPPPS; (SEQ ID NO: 74) Y-Ac4c-QGTFTSDYSIYLDEΨAAKEFIEWLESA; (SEQ ID NO: 83) Y-Ac4c-QGTFTSDYSIALEKΨAQRAFVEWLLAQK; [[Y]] or (SEQ ID NO: 84) Y-Ac4c-QGTFTSDYSIYLDKΨAQRAFVEWLLAQGPSSGAPPPS. - Alternatively, the peptide backbone sequence may differ at up to 5 positions from one of the sequences shown above, within the constraints of Formula I. For the avoidance of doubt, a sequence satisfying the definition of Y1 is regarded as a single position. Typically the compound differs from the reference sequence at only 4 positions in X1 to X29. Thus, if the compound differs from the reference sequence at 5 positions, one of those positions is generally X30 or Y1.
- In particular, the peptide backbone sequence may differ at up to 5 positions from one of the sequences:
-
(SEQ ID NO: 79) Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 60) Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; or (SEQ ID NO: 81) Y-Aib-QGTFTSDYSIALEKΨAQRAFVEWLLAQK. - The peptide backbone of Formula I may have the sequence:
-
(SEQ ID NO: 4) YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)- KAAHDFVEWLLRA; (SEQ ID NO: 27) Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSA; (SEQ ID NO: 28) Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 2) Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSA; (SEQ ID NO: 22) Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- AAKEFVEWLLSA; (SEQ ID NO: 23) Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)- KAAKEFVEWLLSA; (SEQ ID NO: 24) Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)- YLEKKAAKEFVEWLLSA; (SEQ ID NO: 103) Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- AAKEFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 36) Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AAKEFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 37) Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]- isoGlu-Peg3-Peg3)-AAKEFVEWLLSAGPSSGAPPPS; (SEQ ID NO: 32) Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]- isoGlu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS; (SEQ ID NO: 33) Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]- isoGlu)-AQRAFVEWLLAQGPSSGAPPPS; (SEQ ID NO: 34) Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AQRAFVEWLLAQGPSSGAPPPS; (SEQ ID NO: 104) Y-Aib-QGTFTSDYSIYLD-K(eicosanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS; (SEQ ID NO: 44) Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]- isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK; (SEQ ID NO: 45) Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AQRAFVEWLLAQK; (SEQ ID NO: 105) Y-Aib-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]- isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK; (SEQ ID NO: 106) Y-Aib-QGTFTSDLSIALE-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AQRAFVEWLLAQK; (SEQ ID NO: 25) Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- AAKDFIEWLESA; (SEQ ID NO: 29) Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAKDFVEWLESA; (SEQ ID NO: 30) Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAKDFIEWLESA; (SEQ ID NO: 38) Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AAKEFIEWLESA; (SEQ ID NO: 39) Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]- isoGlu-Peg3-Peg3)-AAKEFIEWLESA; (SEQ ID NO: 26) Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLRA; (SEQ ID NO: 96) Y-Aib-QGTFTSDYSIYLE-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AQRAFVEWLLRA; (SEQ ID NO: 97) Y-Aib-QGTFTSDYSIYLE-K([17-carboxy-heptadecanoyl]- isoGlu-Peg3-Peg3)-AQRAFVEWLLRA; (SEQ ID NO: 107) Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-isoGlu-Peg3- Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS; (SEQ ID NO: 108) Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-Dapa-Peg3-Peg3)- AQRAFVNWLVA-Aib-KPSSGAPPPS; (SEQ ID NO: 43) Y-Aib-QGTFTSDYSIALDK-K([19-carboxy-nonadecanoyl]- isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS; (SEQ ID NO: 40) Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]- isoGlu-Peg3-Peg3)-AAKEFIEWLESA; (SEQ ID NO: 109) Y-Ac4c-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]- isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK; or (SEQ ID NO: 51) Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl- isoGlu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS. - Certain of the Y1 groups, when present, may provide increased stability in vivo, e.g. in serum, and so may contribute to the half life of the GIP analogue. Without wishing to be bound by theory, it is believed that these groups may help to stabilize the three dimensional conformation of the molecule and/or provide resistance to proteolytic degradation.
- For example, the Y1 sequences Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:53), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 54), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 55), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 56), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 57) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 58) have homology with a C-terminal portion of the Exendin-4 molecule and appear to contribute to the stability of the molecule without concomitantly providing significant levels of GLP-1 agonist activity.
- The invention further provides a nucleic acid encoding a peptide having the sequence X1-X30 of Formula I. Also provided is an expression construct (also known as an expression vector) comprising a nucleic acid of the invention in operable linkage with suitable regulatory elements to direct expression of the peptide, e.g. transcription and translation. The invention also provides a host cell comprising a nucleic acid or expression construct and capable of expressing, and optionally secreting, the peptide.
- The peptide may itself be a compound of the invention, e.g. when the peptide contains only naturally occurring amino acids (i.e. proteinogenic amino acids), does not contain a residue ψ, and where R1 and R2 are H— and —OH respectively. Alternatively, the peptide may be a precursor of a compound of the invention.
- The invention further provides a pharmaceutical composition comprising a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a carrier, preferably a pharmaceutically acceptable carrier. The triple agonist may, for example, be a pharmaceutically acceptable acid addition salt.
- The pharmaceutical composition may be formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said triple agonist.
- The invention further provides a therapeutic kit comprising a triple agonist as described herein, and a device comprising a triple agonist as described herein.
- The invention further provides a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of medical treatment, e.g. for use in the treatment and/or prevention of a metabolic disorder.
- The invention further provides the use of a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment and/or prevention of a metabolic disorder.
- The invention further provides a method of prevention and or/treatment of a metabolic disorder in a subject, comprising administering a triple agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, to the subject.
- The metabolic disorder may be diabetes or a diabetes related disorder, or obesity or an obesity related disorder. The link between obesity and diabetes is well known, so these conditions are not necessarily separate or mutually exclusive.
- Diabetes related disorders include insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorders and combinations thereof.
- Diabetes related disorders also include atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or conditions associated with atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state and a proinflammatory state.
- Bone related disorders include, but are not limited to osteoporosis and increased risk of bone fracture.
- The blood fat disorder may be selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, and plaque buildup in artery walls, or a combination thereof.
- The prothrombotic state may be selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood.
- The proinflammatory state may be an elevated C-reactive protein level in the blood.
- Obesity related disorders include obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or may be associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a combination thereof.
- Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.
- Unless specified otherwise, the following definitions are provided for specific terms, which are used in the above written description.
- Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).
- The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise.
- The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.
- The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).
- The term “solvate” in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (in casu, a peptide conjugate or pharmaceutically acceptable salt thereof according to the invention) and a solvent. The solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.
- The term “agonist” as employed in the context of the invention refers to a substance (ligand) that activates the receptor type in question.
- Throughout the description and claims the conventional one-letter and three-letter codes for natural (or “proteinogenic”) amino acids are used, as well as generally accepted three letter codes for other (non-natural or “non-proteinogenic”) α-amino acids, such as Aib (α-aminoisobutyric acid), Orn (ornithine) and D-Ala (D-alanine). All amino acid residues in peptides of the invention are preferably of the L-configuration except where explicitly stated.
- Among sequences disclosed herein are sequences incorporating an “H—” moiety at the amino terminus (N-terminus) of the sequence, and either an “—OH” moiety or an “—NH2” moiety at the carboxy terminus (C-terminus) of the sequence. In such cases, and unless otherwise indicated, an “H—” moiety at the N-terminus of the sequence in question indicates a hydrogen atom (i.e. R1═H—), corresponding to the presence of a free primary or secondary amino group at the N-terminus, while an “—OH” or an “—NH2” moiety at the C-terminus of the sequence (i.e. R2═—OH or —NH2) indicates a carboxy (—COOH) group or an amido (—CONH2) group at the C-terminus, respectively.
- Other R1 groups are possible at the N-terminus, including pyroglutamic acid (pGlu; (S)-(−)-2-pyrrolidone-5-carboxylic acid), C1-4 alkyl, acetyl, formyl, benzoyl and trifluoroacetyl.
- Receptor Agonist Activity
- As mentioned above, the compounds described herein are Glucagon-GIP-GLP 1 dual receptor agonists. That is to say, they have agonist activity at all three of the glucagon receptor, the GIP receptor and the GLP-1 receptor.
- The term “agonist” as employed in the context of the invention refers to a substance (ligand) that is capable of binding to a particular receptor and activating signaling by that receptor. Thus a GIP receptor agonist is capable of binding to the GIP receptor (designated GIP-R) and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca2+ release.
- Agonist activity at the GIP receptor may therefore be measured by assessing GIP receptor signalling, which may may, for example, be measured via cAMP production or Ca2+ release.
- The cDNA sequence encoding the human GIP receptor has GenBank accession no. BC101673.1 (GI:75516688). The encoded amino acid sequence (including signal peptide) is:
-
(SEQ ID NO: 111) 1 MTTSPILQLL LRLSLCGLLL QRAETGSKGQ TAGELYQRWE RYRRECQETL AAAEPPSGLA 61 CNGSFDMYVC WDYAAPNATA RASCPWYLPW HHHVAAGFVL RQCGSDGQWG LWRDHTQCEN 121 PEKNEAFLDQ RLILERLQVM YTVGYSLSLA TLLLALLILS LFRRLHCTRN YIHINLFTSF 181 MLRAAAILSR DRLLPRPGPY LGDQALALWN QALAACRTAQ IVTQYCVGAN YTWLLVEGVY 241 LHSLLVLVGG SEEGHFRYYL LLGWGAPALF VIPWVIVRYL YENTQCWERN EVKAIWWIIR 301 TPILMTILIN FLIFIRILGI LLSKLRTRQM RCRDYRLRLA RSTLTLVPLL GVHEVVFAPV 361 TEEQARGALR FAKLGFEIFL SSFQGFLVSV LYCFINKEVQ SEIRRGWHHC RLRRSLGEEQ 421 RQLPERAFRA LPSGSGPGEV PTSRGLSSGT LPGPGNEASR ELESYC (GenBank AAI01674.1 GI: 75516689)”. This may be employed in any assays to determine GIP signalling. - Similarly the compounds have agonist activity at the GLP-1 receptor (GLP-1-R), i.e. they are capable of binding to the GLP-1 receptor and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca2+ release. Agonist activity at the GLP-1 receptor may therefore be measured by assessing GLP-1 receptor signalling, which may may, for example, be measured via cAMP production or Ca2+ release.
- The GLP-1 receptor may have the sequence of the human glucagon-like peptide 1 receptor (GLP-1 R) having primary accession number P43220. The precursor protein (including signal peptide) has primary accession number NP_002053.3; GI:166795283 and has sequence:
-
(SEQ ID NO: 112) 1 MAGAPGPLRL ALLLLGMVGR AGPRPQGATV SLWETVQKWR EYRRQCQRSL TEDPPPATDL 61 FCNRTFDEYA CWPDGEPGSF VNVSCPWYLP WASSVPQGHV YRFCTAEGLW LQKDNSSLPW 121 RDLSECEESK RGERSSPEEQ LLFLYIIYTV GYALSFSALV IASAILLGFR HLHCTRNYIH 181 LNLFASFILR ALSVFIKDAA LKWMYSTAAQ QHQWDGLLSY QDSLSCRLVF LLMQYCVAAN 241 YYWLLVEGVY LYTLLAFSVL SEQWIFRLYV SIGWGVPLLF VVPWGIVKYL YEDEGCWTRN 301 SNMNYWLIIR LPILFAIGVN FLIFVRVICI VVSKLKANLM CKTDIKCRLA KSTLTLIPLL 361 GTHEVIFAFV MDEHARGTLR FIKLFTELSF TSFQGLMVAI LYCFVNNEVQ LEFRKSWERW 421 RLEHLHIQRD SSMKPLKCPT SSLSSGATAG SSMYTATCQA SCS. - Similarly the compounds have agonist activity at the glucagon receptor (Glu-R), i.e. they are capable of binding to the glucagon receptor and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca2+ release. Agonist activity at the glucagon receptor may therefore be measured by assessing glucagon receptor signalling, which may, for example, be measured via cAMP production or Ca2+ release.
- The glucagon receptor may have the sequence of the human glucagon receptor (Glu-R) having primary accession number P47871. The precursor protein (including signal peptide) has primary accession number NP_000151.1; GI:4503947, and has the sequence:
-
(SEQ ID NO: 113) 1 MPPCQPQRPL LLLLLLLACQ PQVPSAQVMD FLFEKWKLYG DQCHHNLSLL PPPTELVCNR 61 TFDKYSCWPD TPANTTANIS CPWYLPWHHK VQHRFVFKRC GPDGQWVRGP RGQPWRDASQ 121 CQMDGEEIEV QKEVAKMYSS FQVMYTVGYS LSLGALLLAL AILGGLSKLH CTRNAIHANL 181 FASFVLKASS VLVIDGLLRT RYSQKIGDDL SVSTWLSDGA VAGCRVAAVF MQYGIVANYC 241 WLLVEGLYLH NLLGLATLPE RSFFSLYLGI GWGAPMLFVV PWAVVKCLFE NVQCWTSNDN 301 MGFWWILRFP VFLAILINFF IFVRIVQLLV AKLRARQMHH TDYKFRLAKS TLTLIPLLGV 361 HEVVFAFVTD EHAQGTLRSA KLFFDLFLSS FQGLLVAVLY CFLNKEVQSE LRRRWHRWRL 421 GKVLWEERNT SNHRASSSPG HGPPSKELQF GRGGGSQDSS AETPLAGGLP RLAESPF - In all cases, where sequences of precursor proteins are referred to, it should of course be understood that assays may make use of the mature protein, lacking the signal sequence.
- The compounds of the present invention have at least one GIP, one glucagon, and one GLP-1 biological activity, in particular in treatment of metabolic diseases such as diabetes and obesity. This can be assessed, e.g., in in vivo assays, for example as described in the examples, in which the blood glucose level or another biological activity is determined after a test animal has been treated or exposed to a triple agonist. In particular, compounds of the invention may be capable of improving glycaemic control when adminstered to a diabetic subject. Additionally or alternatively, they may be capable of reducing body weight when administered to an overweight or obese subject. In either case, the effect may be superior to that obtained with an equivalent quantity (by mass, or molar ratio) of wild type human GIP or GLP-1 in comparable subjects when given according to a comparable dosing regime.
- Activity in in vitro assays may also be used as a measure of the compounds' activity. Typically the compounds have activity at the glucagon, GLP-1 and GIP receptors (designated GCG-R, GLP-1-R and GIP-R respectively). EC50 values may be used as a numerical measure of agonist potency at a given receptor. An EC50 value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay. Thus, for example, a compound having EC50[GLP-1R] lower than the EC50[GLP-1 R] of native GIP in a particular assay may be considered to have higher potency at the GLP-1R than GIP. In some embodiments of the present invention, the EC50 GLP-1-R and/or EC50 GIP-R and/or EC50 GCG-R is below 1.0 nM, below 0.9 nM, below 0.8 nM, below 0.7 nM, below 0.6 nM, below 0.5 nM, below 0.4 nM, below 0.3 nM, below 0.2 nM, below 0.1 nM, below 0.09 nM, below 0.08 nM, below 0.07 nM, below 0.06 nM, below 0.05 nM, below 0.04 nM, below 0.03 nM, below 0.02 nM, below 0.01 nM, below 0.009 nM, below 0.008 nM, below 0.007 nM, below 0.006 nM, or below 0.005 nM, e.g. when assessed using the assay described in Example 2.
- Lipophilic Group
- The compound of the invention may comprise a residue ψ, i.e. a residue selected from Lys, Arg, Orn and Cys in which the side chain is conjugated to a lipohilic substituent.
- Without wishing to be bound by any particular theory, it is thought that the substituent binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the compounds of the invention from enzymatic degradation and renal clearance and thereby enhancing the half-life of the compounds. It may also modulate the potency of the compound, e.g. with respect to the GIP receptor, the glucagon receptor and/or the GLP-1 receptor.
- The substituent is conjugated to the functional group at the distal end of the side chain from the alpha-carbon. The normal ability of the Lys, Arg, Orn or Cys side chain to participate in interactions mediated by that functional group (e.g. intra- and inter-molecular interactions) may therefore be reduced or completely eliminated by the presence of the substituent. Thus, the overall properties of the compound may be relatively insensitive to changes in the actual amino acid present as residue ψ. Consequently, it is believed that any of the residues Lys, Arg, Orn and Cys may be present at any position where ψ is permitted. However, in certain embodiments, it may be advantageous that the amino acid component of ψ is Lys.
- Thus, ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z1 or —Z2—Z1.
- —Z1 is a fatty chain having at a terminus a connection —X— to ψ or to Z2;
- wherein
- —X— is a bond, —CO—, —SO—, or —SO2—;
- and, optionally, Z1 has a polar group at the end of the chain distal from connection —X—; said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;
- and wherein —Z2—, if present, is a spacer of formula:
- connecting Z1 to ψ;
- wherein:
- each Y is independently —NH, —NR, —S or —O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z2;
- each X is independently a bond, CO—, SO—, or SO2—;
- with the proviso that when Y is —S, the X to which it is bound is a bond;
- each V is independently a bivalent organic moiety linking Y and X;
- and n is 1-10.
- The group Z1
- Z1 is a fatty chain having a connection to ψ or to Z2, referred to herein as —X—. —X— may be, for example, a bond, acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO2—). When Z1 is bound directly to ψ, that is, when Z2 is not present, preferably —X— is acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO2—). Most preferably, —X— is acyl (—CO—).
- Z1 may further have a polar group, said polar group being located at the end of the chain distal from the connection —X—. In other words, the connection is located at the ω-position with respect to the polar group. The polar group may be bound directly to the terminus of the fatty chain, or may be bound via a linker.
- Preferably, the polar group is an acidic or weakly acid group, for example a carboxylic acid or a carboxylic acid bioisostere, a phosphonate, or a sulfonate. The polar group may have a pKa of between −2 and 12 in water, more preferably between 1 and 7, more preferably between 3 and 6. Certain preferred polar groups have a pKa of between 4 and 5.
- For example, and not by way of limitation, the polar group may comprise a carboxylic acid (—COOH) or a carboxylic acid bioisostere, a phosphonic acid (—P(O)(OH)2), or a sulfonic acid (—SO2OH) group.
- Preferably the polar group, if present, comprises a carboxylic acid or carboxylic acid bioisostere. Suitable carboxylic acid bioisosteres are known in the art. Preferably the bioisostere has a proton having a pKa similar to the corresponding carboxylic acid. Examples of suitable bioisoteres may include, not by way of limitation, tetrazole, acylsulfomides, acylhydroxylamine, and squaric acid derivatives, as shown below (--- indicates the point of attachment):
- Fatty chain as used herein refers to a moiety comprising a chain of carbon atoms, the carbon atoms being predominantly substituted with hydrogen or hydrogen-like atoms, for example, a hydrocarbon chain. Such fatty chains are often referred to as lipophilic, although it will be appreciated that substitution may alter the lipophilic properties of the overall molecule.
- The fatty chain may by aliphatic. It may be entirely saturated or may include one or more double or triple bonds. Each double bond, if present, may be in the E or Z configuration. The fatty chain may also have one or more cycloalkylene or heterocycloalkylene moieties in its length, and additionally or alternatively may have one or more arylene or heteroarylene moieties in its length. For example, the fatty chain may incorporate a phenylene or piperazinylene moiety in its length as, for example, shown below (wherein --- represents the points of attachment within the chain).
- The fatty chain may be derived from a fatty acid, for example, it may be derived from a medium-chain fatty acid (MCFA) with an aliphatic tail of 6-12 carbon atoms, a long-chain fatty acid (LCFA) with an aliphatic tail of 13-21 carbon atoms, or a very long-chain fatty acid (LCFA) with an aliphatic tail of 22 carbon atoms or more. Examples of linear saturated fatty acids from which suitable fatty chains may be derived include tridecylic (tridecanoic) acid, myristic (tetradecanoic) acid, pentadecylic (pentadecanoic) acid, palmitic (hexadecanoic) acid, and margaric (heptadecanoic) acid. Examples of linear unsaturated fatty acids from which suitable fatty chains may be derived include myristoleic acid, palmitoleic acid, sapienic acid and oleic acid.
- The fatty chain may be connected to ψ or to Z2 by an amide linkage, a sulfinamide linkage, a sulfonamide linkage, or by an ester linkage, or by an ether, thioether or amine linkage. Accordingly, the fatty chain may have, a bond to ψ or to Z2 or an acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO2—) group. Preferably, the fatty chain has a terminus having an acyl (—CO—) group and is connected to ψ or Z2 by an amide or ester linkage.
- In some embodiments, Z1 is a group of formula:
-
A-B-Alk-X— - wherein
- A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;
- B is a bond or a linker;
- X is a bond, acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO2—); and
- Alk is a fatty chain that may be optionally substituted with one or more substituents. The fatty chain is preferably 6 to 28 carbon atoms in length (e.g. a C6-28alkylene), more preferably, 12 to 26 carbons in length (e.g. a C12-26alkylene), more preferably, 16 to 22 carbons in length (e.g. C16-22alkylene), and may be saturated or unsaturated. Preferably, Alk is saturated, that is, preferably Alk is alkylene.
- Optional substituents on the fatty chain may be independently selected from fluoro, C1-4alkyl, preferably methyl; trifluoromethyl, hydroxymethyl, amino, hydroxyl, C1-4alkoxy, preferably methoxy; oxo, and carboxyl, and may be independently located at any point along the chain. In some embodiments, each optional substituent is selected from fluoro, methyl, and hydroxyl. Where more than one substituent is present, substituents may be the same or different. Preferably, the number of substituents is 0 to 3; more preferably the fatty chain is unsubstituted.
- B may be a bond or a linker. When B is a linker, it may be a cycloalkylene, heterocycloalkylene, C6arylene, or C5-6heteroarylene, or C6arylene-O— or C5-6heteroarylene-O—.
- When B is phenylene it may, for example, be selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, preferably 1,4-phenylene (so that A-B— is a 4-benzoic acid substituent or 4-benzoic acid bioisostere). When B is phenylene-O—, it may, for example, be selected from 1,2-phenylene-O—, 1,3-phenylene-O—, 1,4-phenylene-O—, preferably 1,4-phenylene-O. Each phenylene of B may be optionally substituted with one or more substituents selected from fluoro, methyl, trifluoromethyl, amino, hydroxyl, and C1-4alkoxy, preferably methoxy. It will be appreciated that substituent identity and position may be selected to subtly alter the pKa of the polar group. Suitable inductively or mesomerically electron-withdrawing or donating groups and their positional effects are known in the art. In some embodiments, B may be C5-6heteroarylene, for example, pyridinylene or thiofuranylene, and may be optionally substituted as described.
- For example, in some embodiments, A-B— may be selected from:
- Preferably, is H— or HOOC— and B is a bond.
- It will be understood that when A is hydrogen, B is a bond and Alk is unsubstituted alkylene, A-B-Alk- is an alkyl chain of formula H3C—(CH2)n—.
- In some embodiments, Z1 is an acyl group of formula:
-
A-B-Alk-(CO)— - or a sulfonyl group of formula:
-
A-B-Alk-(SO2)—. - Preferably, Z1 is an acyl group of formula:
-
A-B-alkylene-(CO)— - where A and B are as defined above.
- In some embodiments, A is —COOH and B is a bond. Accordingly, certain preferred Z1 are derived from long-chain saturated α,ω-dicarboxylic acids of formula HOOC—(CH2)12-22—COOH, preferably, long-chain saturated α,ω-dicarboxylic acids having an even number of carbon atoms in the aliphatic chain. In some other embodiments, A is H and B is a bond. Accordingly, certain preferred Z1 are derived from long-chain saturated carboxylic acids of formula HOOC—(CH2)12-22—CH3, preferably, long-chain saturated carboxylic acids having an even number of carbon atoms in the aliphatic chain.
- For example, and not by way of limitation, Z1 may be:
- A-B-C16-20alkylene-(CO)— wherein A is H or —COOH and B is a bond, for example:
- 17-carboxy-heptadecanoyl HOOC—(CH2)16—(CO)—;
- 19-carboxy-nonadecanoyl HOOC—(CH2)13—(CO)—;
- Octadecanoyl H3C—(CH2)16—(CO)—;
- Eicosanoyl H3C—(CH2)18—(CO)—;
- The carboxylic acid group, if present, may be replaced by a bioisotere as detailed herein.
- The Group Z2
- Z2 is an optional spacer that connects Z1 to the side chain of the amino acid component of ψ. At its most general, Z2, if present, is a spacer bound at one terminus by Y, which may be a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which may be a bond or an acyl (—CO—), sulfinyl (—SO—), sulfonyl (—SO2—) or absent. Accordingly, Z2 may be a spacer of formula (--- indicate points of attachment):
- wherein:
- Y may be —NH, —NR, —S or —O, where R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z1;
- X may be a bond, CO—, SO—, or SO2—, with the remaining valency forming a linkage to the side chain of the amino acid component of Y;
- V is a bivalent organic moiety linking Y and X;
- and n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Where n is 2 or more, each Y, V, and X is independent of every other Y, V, and X.
- Accordingly, Z2 may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z1 and the side chain. Where n is 2 or greater, each V may also be bound to each adjacent V by linkages as described. Preferably, linkages are amides, esters or sulfonamides, most preferably amides. Accordingly, in some embodiments, each Y is —NH or —NR and each X is CO— or SO2—. Most preferably, —X— is acyl (—CO—).
- In some embodiments, Z2 is a spacer of formula —SA—, —SB—, —SA—SB— or —SB—SA—, wherein SA and SB are as defined below.
- In some embodiments, Z2 is selected from —SA— or —SB—SA—, that is, [side chain]—Z2Z1 is [side chain]—SA—Z1 or [side chain]—SB—SA—Z1.
- The Group SA
- SA may be a single amino acid residue or a residue of an amino acid derivative, especially an amino acid derivative residue having a sulfinyl or sulfonyl in place of the carboxy moiety at the C terminus. Additionally or alternatively, the single amino acid residue may have an oxygen or sulfur atom in place of the nitrogen atom at the N terminus. Preferably, SA is a single amino acid residue.
- In some embodiments, the amino acid may be selected from γ-Glu, α-Glu, α-Asp, β-Asp, Ala, β-Ala (3-aminopropanoic acid), Dapa (2,3-diaminopropanoic acid), Dab (2,4-diaminobutanoic acid), and Gaba (4-aminobutanoic acid). It will be understood that where more than one carboxylic acid or amino moiety is present, connection may be at any moiety as appropropriate. Any carboxylic acid or amino resides not bound within the residue may be free, that is, present as a free carboxylic acid or primary amine, or may be derivatised. Suitable derivatisation is known in the art. For example, carboxylic acid moieties may be present in SA amino acid residues as esters, for example, as methyl esters. Amino moieties may be present as alkylated amines, for example, methylated, or may be protected as amide or carbamate moieties. Other suitable amino acids include β-Ala (3-aminopropanoic acid) and Gaba (4-aminobutanoic acid) and similar w amino acids.
- It will be understood that amino acids may be D or L, or a racemic or enantioenriched mixture. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid.
- In some preferred embodiments, SA has a carboxylic acid substituent, with γ-Glu, α-Glu, α-Asp, and β-Asp, and sulfinyl and sulfonyl derivatives thereof, being preferred. Accordingly, in some embodiments, the amino acid residue is:
- where —X— is —CO—, —SO—, —SO2—, preferably —CO—, and a is 1 or 2, preferably 2. In some embodiments, the carboxylic acid is an ester, and the amino acid residue is:
- where —X— is —CO—, —SO—, —SO2—, preferably —CO—, and a is 1 or 2, preferably 2, and R is C1-4alkyl or C6aryl. Preferably R is C1-4alkyl, preferably methyl or ethyl, more preferably ethyl.
- A preferred SA group bearing a carboxylic acid is γ-Glu.
- Preferably, SA is selected from Dapa or γ-Glu. Most preferably, SA is γ-Glu.
- The Group SB
- SB may be a linker of general formula:
- wherein PU is a polymeric unit and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. One terminus of the linker SB is an —NH, —NR, —S or —O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the polymeric unit; while the other is a bond or CO—, SO— or SO2—. Accordingly, each polymeric unit PU may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z1, SA, and Lys.
- In some embodiments, each PU may be independently a unit of formula:
- wherein:
- Y may be —NH, —NR, —S or —O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z1;
- X may be a bond, CO—, SO—, or SO2—, with the remaining valency forming a linkage to the ψ side chain;
- and V is a bivalent organic moiety linking Y and X.
- In some embodiments, V is the α-carbon of a natural or unnatural amino acid, that is V is —CHRAA—, wherein RAA is an amino acid side chain; or V is an optionally substituted C1-6alkylene, or V is a chain comprising one or more units of ethylene glycol in series, also known as PEG chain, for example, —CH2CH2—(OCH2CH2)m—O—(CH2)p—, where m is 0, 1, 2, 3, 4, or 5, and p is 1, 2, 3, 4, or 5; when X is CO—, p is preferably 1, 3, 4, or 5. Optional alkylene substituents include fluoro, methyl, hydroxy, hydroxymethy, and amino.
- Preferred PU units include:
- (i). Single amino acid residues: PU i;
- (ii). Dipeptide residues: PU ii; and
- (iii). Amino-(PEG)m-carboxylic acid residues: PU iii,
- and may be present in any combination or order. For example, SB may comprise one or more of each of PU i, PU ii, and PU ii in any order, or may comprise one or more units of PU i, PU ii, and PU i only, or one of more units selected from PU i and PU ii, PU i and PU iii, or PU ii and PU iii.
- (1). PU i single amino acid residues
- Each PU i may be independently selected from any natural or unnatural amino acid residue and, for example, may be selected from Gly, Pro, Ala, Val, Leu, lie, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, Asp, Ser Thr, Dapa, Gaba, Aib, β-Ala, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, and 10-aminodecanoyl. Preferably, PU i amino acid residues are selected from Gly, Ser, Ala, Thr, and Cys, more preferably from Gly and Ser.
- In some embodiments, SB is —(PU i)n—, wherein n is 1 to 8, more preferably 5 to 7, most preferably 6. In some preferred embodiments, SB is —(PU i)n—, n is 6 and each PU i is independently selected from Gly or Ser, with a preferred sequence being -Gly-Ser-Gly-Ser-Gly-Gly- (SEQ ID NO: 114).
- (ii). PU ii dipeptide residues Each PU i may be independently selected from any dipeptide residue comprising two natural or unnatural amino acid residues bound by an amide linkage. Preferred PU ii dipeptide residues include Gly-Gly, Gly-Ser, Ser-Gly, Gly-Ala, Ala-Gly, and Ala-Ala, more preferably Gly-Ser and Gly-Gly.
- In some embodiments, SB is —(PU ii)n—, wherein n is 2 to 4, more preferably 3, and each PU ii is independently selected from Gly-Ser and Gly-Gly. In some preferred embodiments SB is —(PU ii)n—, n is 3 and each PU i is independently selected from Gly-Ser and Gly-Gly, with a preferred sequence being -(Gly-Ser)-(Gly-Ser)-(Gly-Gly) (SEQ ID NO: 114).
- Amino acids having stereogenic centres within PU i and PU ii may be racemic, enantioenriched, or enantiopure. In some embodiments, the or each amino acid is independently an L-amino acid.
- In some embodiments, the or each amino acid is independently a D-amino acid.
- (iii). PU iii amino-(PEG)m-carboxylic acid residues
- Each PU iii may be independently a residue of general formula:
- wherein m is 0, 1, 2, 3, 4, or 5, preferably 1 or 2, and p is 1, 3, 4, or 5, preferably 1.
- In some embodiments, m is 1 and p is 1, that is, PU iii is a residue of 8-amino-3,6-dioxaoctanoic acid (also known as {2-[2-aminoethoxy]ethoxy}acetic acid and H2N-PEG3-COOH). This residue is referred to herein as -PEG3-.
- Other, longer, PEG chains are also known in the art. For example, 11-amino-3,6,9-trioxaundecanoic acid (also known as H2N-PEG4-COOH or -PEG4-).
- In some embodiments, SB is —(PU iii)n—, wherein n is 1 to 3, more preferably 2.
- Most preferably, SB is -PEG3-PEG3-.
- Preferred Combinations
- It will be understood that the above preferences may be independently combined to give preferred —Z1 and —Z2—Z1 moieties.
- Some preferred —Z1 and —Z2—Z1 moieties are shown below (in each case, -- indicates the point of attachment to the side chain of the amino acid component of ψ:
- The skilled person will be well aware of suitable techniques for preparing the compounds employed in the context of the invention. For examples of suitable chemistry, see, e.g., WO98/08871, WO00/55184, WO00/55119, Madsen et al. (J. Med. Chem. 2007, 50, 6126-32), and Knudsen et al. 2000 (J. Med Chem. 43, 1664-1669).
- Clinical Utility
- The compounds of the invention may provide an attractive treatment option for metabolic diseases including obesity and diabetes mellitus (diabetes). Diabetes comprises a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Acute signs of diabetes include excessive urine production, resulting compensatory thirst and increased fluid intake, blurred vision, unexplained weight loss, lethargy, and changes in energy metabolism. However, symptoms are often not severe or may be absent. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart and blood vessels. Diabetes is classified into type 1 diabetes, type 2 diabetes and gestational diabetes on the basis on pathogenetic characteristics. Type 1 diabetes accounts for 5-10% of all diabetes cases and is caused by auto-immune destruction of insulin-secreting pancreatic β-cells.
- Type 2 diabetes accounts for 90-95% of diabetes cases and is a result of a complex set of metabolic disorders. However, symptoms are often not severe or may be absent. Type 2 diabetes is the consequence of endogenous insulin production becoming insufficient to maintain plasma glucose levels below diagnostic thresholds.
- Gestational diabetes refers to any degree of glucose intolerance identified during pregnancy.
- Pre-diabetes includes impaired fasting glucose and impaired glucose tolerance and refers to those states that occur when blood glucose levels are elevated but below the levels that are established for the clinical diagnosis for diabetes.
- A large proportion of people with type 2 diabetes and pre-diabetes are at increased risk of morbidity and mortality due to the high prevalence of additional metabolic risk factors, including abdominal obesity (excessive fat tissue around the abdominal internal organs), atherogenic dyslipidemia (blood fat disorders including high triglycerides, low HDL cholesterol and/or high LDL cholesterol, which foster plaque buildup in artery walls), elevated blood pressure (hypertension) a prothrombotic state (e.g. high fibrinogen or plasminogen activator inhibitor- 1 in the blood), and/or a proinflammatory state (e.g., elevated C-reactive protein in the blood).
- Conversely, obesity confers an increased risk of developing pre-diabetes, type 2 diabetes as well as, e.g., certain types of cancer, obstructive sleep apnea and gall-bladder disease.
- Dyslipidemia is associated with increased risk of cardiovascular disease. High Density Lipoprotein (HDL) is of clinical importance since an inverse correlation exists between plasma HDL concentrations and risk of atherosclerotic disease. The majority of cholesterol stored in atherosclerotic plaques originates from LDL and hence an elevated concentration of Low Density Lipoproteins (LDL) is closely associated with atherosclerosis. The HDL/LDL ratio is a clinical risk indictor for atherosclerosis and coronary atherosclerosis in particular.
- Compounds employed in the context of the invention act as glucagon-GIP-GLP1 triple agonists. The triple agonist may combine the effect of glucagon, e.g., on fat metabolism with the effect of GIP on improved glycemic control and the effect of GLP-1 e.g., on blood glucose levels and food intake. They may therefore act to accelerate elimination of excessive adipose tissue, induce sustainable weight loss, and improve glycemic control. Triple glucagon-GIP-GLP1 agonists may also act to reduce cardiovascular risk factors such as high cholesterol and such as high LDL-cholesterol.
- The triple agonist compounds of the present invention may therefore be used (alone or in combination) as pharmaceutical agents for preventing weight gain, promoting weight loss, reducing excess body weight or treating obesity (e.g., by control of appetite, feeding, food intake, calorie intake, and/or energy expenditure and lipolysis), including morbid obesity, as well as associated diseases and health conditions including but not limited to obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea. The compounds may also be used for treatment of insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, dyslipidemia (or a combination of these metabolic risk factors), atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke. These are all conditions which may be associated with obesity. However, the effects of the compounds employed in the context of the invention on these conditions may be mediated in whole or in part via an effect on body weight, or may be independent thereof.
- The triple agonist compounds may thus be used (alone or in combination) for the treatment and/or prevention of any of the diseases, disorders, or conditions described herein, including insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof. In certain embodiments, the diabetes related disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and proinflammatory state, or a combination thereof. In certain embodiments, the blood fat disorder is selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof. In certain embodiments, the prothrombotic state is selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood. In certain embodiments, the proinflammatory state is an elevated C-reactive protein level in the blood. In certain embodiments, the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.
- The triple agonist compounds may also be used for the treatment and/or prevention of any of the diseases, disorders, or conditions associated with diabetes related osteoporosis including increased risk of bone fractures. The observed increase in fracture risk is likely to be related to impaired bone quality rather than to bone mineral density. The related mechanisms, due at least in part to hyperglycemia, neuropathy, and higher incidence of hypovitaminosis D, are not yet fully understood.
- The invention provides the use of a triple agonist compound as described, in the manufacture of a medicament for any of the clinical applications described in this specification. Reference to a compound for use in any such method should be construed accordingly.
- In some embodiments, the invention also provides a therapeutic kit comprising a triple agonist of the invention, optionally in combination with a pharmaceutically acceptable carrier. In some embodiments, the invention provides a device comprising a triple agonist of the invention for delivery of the triple agonist to a subject.
- Pharmaceutical Compositions
- The triple agonist compounds of the present invention, or salts or solvates thereof, may be formulated as pharmaceutical compositions prepared for storage or administration, which typically comprise a therapeutically effective amount of a compound employed in the context of the invention, or a salt or solvate thereof, in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of the triple agonist compound
- The therapeutically effective amount of a compound of the present invention will depend, e.g., on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts. The dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials.
- An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person. The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, sterile saline and phosphate- buffered saline at slightly acidic or physiological pH may be used. Suitable pH buffering agents may be, e.g., phosphate, citrate, acetate, lactate, maleate, tris/hydroxymethyl)aminomethane (TRIS), N-Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof. The term further encompasses any agents listed in the US Pharmacopeia for use in animals, including humans.
- The term “pharmaceutically acceptable salt” refers to a salt of the compound. Salts include pharmaceutically acceptable salts, such as, e.g., acid addition salts and basic salts. Examples of acid addition salts include hydrochloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals such as calcium, and ammonium ions +N(R3)3(R4), where R3 and R4 independently designate optionally substituted C1-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. Other examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences”, 17th edition. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and more recent editions, and in the Encyclopaedia of Pharmaceutical Technology.
- “Treatment” is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” may also mean prolonging survival as compared to expected survival if not receiving treatment. “Treatment” is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. Accordingly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures in certain embodiments. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. By treatment is meant inhibiting or reducing an increase in pathology or symptoms (e.g. weight gain, hyperglycemia) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition.
- The pharmaceutical compositions of the invention may be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. It may be provided in single dose injectable form, for example in the form of an injection pen. Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Subcutaneous or transdermal modes of administration may be particularly suitable for certain of the compounds described herein.
- Combination Therapy
- In certain embodiments, a compound of the invention may be administered as part of a combination therapy with at least one other agent for treatment of diabetes, obesity, dyslipidemia, or hypertension.
- In such cases, the at least two active agents may be given together or separately, and as part of the same pharmaceutical formulation or as separate formulations. Thus, the triple agonist compound (or the salt or solvate thereof) may be used in combination with an antidiabetic agent including but not limited to metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, or insulin. In certain embodiments, the compound or salt or solvate thereof is used in combination with insulin, DPP-IV inhibitor, sulfonylurea or metformin, particularly sulfonylurea or metformin, for achieving adequate glycemic control. In certain preferred embodiments, the compound or salt or solvate thereof is used in combination with insulin or an insulin analogue for achieving adequate glycemic control. Examples of insulin analogues include but are not limited to LANTUS®, NOVORAPID®, HUMALOG®, NOVOMIX®, ACTRAPHANE HM®, LEVEMIR® and APIDRA®.
- In certain embodiments, the triple agonist compound or salt or solvate thereof may further be used in combination with one or more of an anti-obesity agent, including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist.
- In certain embodiments, the triple agonist compound or salt or solvate thereof may be used in combination with an anti-hypertension agent, including but not limited to an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretics, beta-blocker, or calcium channel blocker.
- In certain embodiments, the triple agonist compound or salt thereof may be used in combination with an anti-dyslipidemia agent, including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.
- Nucleic Acids, Vectors, and Host Cells
- The invention provides a nucleic acid encoding a peptide having the sequence X1-X30 of Formula I. Also provided is an expression construct (also known as an expression vector) comprising a nucleic acid of the invention in operable linkage with suitable regulatory elements to direct expression of the peptide, e.g. transcription and translation. The invention also provides a host cell comprising a nucleic acid or expression construct and capable of expressing, and optionally secreting, the peptide.
- In some embodiments, the invention provides a method of producing a compound of the invention, the method comprising culturing the host cells described above under conditions suitable for expressing the compound and purifying the compound thus produced.
- The invention also provides a nucleic acid molecule, an expression vector, or a host cell, as described above, for use in a method of medica treatment, and in particular for treatment of the metabolic disorders discussed elsewhere in this specification.
- Synthesis of Compounds of the Invention
- A nucleic acid molecule may encode a compound of the invention, a peptide having the amino acid sequence X1-X30 of Formula I, or a peptide which is a precursor of a compound of the invention.
- Typically, such nucleic acid sequences will be provided as expression constructs wherein the encoding nucleic acid is in functional linkage with appropriate control sequences to direct its expression. The expression construct may be provided in the context of a host cell capable of expressing (and optionally also secreting) the =precursor, or in a cell-free expression system.
- The invention provides a method of producing a triple agonist of the invention, the method comprising expressing an amino acid precursor of the triple agonist and modifying the precursor to provide the triple agonist. The modification may comprise chemical modification of a Lys, Arg or Cys residue present at a position ψ to introduce the lipophilic moiety, modification of the N- or C-terminus, and/or modification of any other amino acid side chains in the molecule (e.g. to introduce a non-naturally occurring amino acid residue).
- The compounds of the invention may also be manufactured by standard peptide synthetic methods, e.g. by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and isolating and purifying the final peptide compound product, or by any combinations of recombinant and synthetic methods.
- It may be preferable to synthesize the peptide compounds of the invention by means of solid-phase or liquid-phase peptide synthesis. In this context, reference may be made to WO 98/11125 or, inter alia, Fields, G. B. et al., “Principles and Practice of Solid-Phase Peptide Synthesis”; in: Synthetic Peptides, Gregory A. Grant (ed.), Oxford University Press (2nd edition, 2002) and the synthesis examples herein.
- The following examples demonstrate certain embodiments of the present invention. However, it is to be understood that these examples neither purport nor are they intended to be wholly definitive as to conditions and scope of this invention. The examples were carried out using standard techniques, which are well known and routine to those of skill in the art, except where otherwise described in detail. The following examples are presented for illustrative purposes only, and should not be construed in any way as limiting the scope of this invention.
- All publications, patents, and patent applications referred to herein are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
- The methods used in the instant invention are described below, except where expressly indicated otherwise.
- General Synthesis of Acylated Triple Agonists Solid phase peptide synthesis was performed on a CEM Liberty Peptide Synthesizer using standard Fmoc chemistry. TentaGel S Ram resin (1 g; 0.25 mmol/g) was swelled in NMP (10 ml) prior to use and transferred between tube and reaction vessel using DCM and NMP.
- Coupling
- An Fmoc-amino acid in NMP/DMF/DCM (1:1:1; 0.2 M; 5 ml) was added to the resin in a CEM Discover microwave unit together with COMU/NMP (0.5 M; 2 ml) and DIPEA/DMF (2.0 M; 1 ml). The coupling mixture was heated to 75° C. for 5 min while nitrogen was bubbled through the mixture. The resin was then washed with DMF (4×10 ml).
- Deprotection
- Piperidine/NMP (20%; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40° C.). The reaction vessel was drained and a second portion of piperidine/DMF (20%; 10 ml) was added and heated (75° C.; 3 min.) again. The resin was then washed with NMP (6×10 ml).
- Side Chain Acylation
- Fmoc-Lys(ivDde)-OH or alternatively another amino acid with an orthogonal side chain protective group was introduced at the position of the acylation. The N-terminal of the peptide backbone was then Boc-protected using Boc2O or alternatively by using a Boc-protected amino acid in the last coupling. While the peptide was still attached to the resin, the orthogonal side chain protective group was selectively cleaved using freshly prepared hydrazine hydrate (2-4%) in NMP for 2×15 min. The unprotected lysine side chain was first coupled with Fmoc-Glu-OtBu or another spacer amino acid, which was deprotected with piperidine and acylated with a lipophilic moiety using the peptide coupling methodology as described above. Abbreviations employed are as follows:
- COMU: 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholinomethylene)]methanaminium hexafluorophosphate
- ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl
- Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl
- DCM: dichloromethane
- DMF: N,N-dimethylformamide
- DIPEA: diisopropylethylamine
- EtOH: ethanol
- Et2O: diethyl ether
- HATU: N-[(dimethylamino)-1H-1,2,3-triazol[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
- MeCN: acetonitrile
- NMP: N-methylpyrrolidone
- TFA: trifluoroacetic acid
- TIS: triisopropylsilane
- Cleavage
- The resin was washed with EtOH (3×10 ml) and Et2O (3×10 ml) and dried to constant weight at room temperature (r.t.). The crude peptide was cleaved from the resin by treatment with TFA/TIS/water (95/2.5/2.5; 40 ml, 2 h; r.t.). Most of the TFA was removed at reduced pressure and the crude peptide was precipitated and washed three times with diethylether and dried to constant weight at room temperature.
- HPLC Purification of the Crude Peptide
- The crude peptide was purified to greater than 90% by preparative reverse phase HPLC using a PerSeptive Biosystems VISION Workstation equipped with a C-18 column (5 cm; 10 μm) and a fraction collector and run at 35 ml/min with a gradient of buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.). Fractions were analyzed by analytical HPLC and MS and relevant fractions were pooled and lyophilized. The final product was characterized by HPLC and MS. The synthesized compounds are shown in Table 1:
-
TABLE 1 Compound No Sequence 1 H-YSQGTFTSDYSKYLDSKAAHDFVEWLLRA-NH2 (SEQ ID NO: 1) 2 H-Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSA-NH2 (SEQ ID NO: 2) 3 H-Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA-NH2 (SEQ ID NO: 3) 4 H-YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-KAAHDFVEWLLRA- NH2 (SEQ ID NO: 4) 5 H-Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA-NH2 (SEQ ID NO: 5) 6 H-Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA-NH2 (SEQ ID NO: 6) 7 H-Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA-NH2 (SEQ ID NO: 7) 8 H-Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA-NH2 (SEQ ID NO: 8) 9 H-Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA-NH2 (SEQ ID NO: 9) 10 H-Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA-NH2 (SEQ ID NO: 10) 11 H-Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA-NH2 (SEQ ID NO: 11) 12 H-Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA-NH2 (SEQ ID NO: 12) 13 H-Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS-NH2 (SEQ ID NO: 13) 14 H-Y-Aib-QGTFTSDYSIYLE-KKAAHDFVEWLLSA-NH2 (SEQ ID NO: 14) 15 H-Y-Aib-QGTFTSDYSIYLE-KKAAHDFVEWLLSA-NH2 (SEQ ID NO: 14) 16 H-Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA-NH2 (SEQ ID NO: 15) 17 H-Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA-NH2 (SEQ ID NO: 16) 18 H-Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA-NH2 (SEQ ID NO: 17) 19 H-Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA-NH2 (SEQ ID NO: 18) 20 H-Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA-NH2 (SEQ ID NO: 19) 21 H-Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA-NH2 (SEQ ID NO: 20) 22 H-Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA-NH2 (SEQ ID NO: 21) 23 H-Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- AAKEFVEWLLSA-NH2 (SEQ ID NO: 22) 24 H-Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)- KAAKEFVEWLLSA-NH2 (SEQ ID NO: 23) 25 H-Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)- YLEKKAAKEFVEWLLSA-NH2 (SEQ ID NO: 24) 26 H-Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- AAKDFIEWLESA-NH2 (SEQ ID NO: 25) 27 H-Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLRA-NH2 (SEQ ID NO: 26) 28 H-Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSA-NH2 (SEQ ID NO: 27) 29 H-Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- AAHDFVEWLLSAGPSSGAPPPS-NH2 (SEQ ID NO: 28) 30 H-Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAKDFVEWLESA-NH2 (SEQ ID NO: 29) 31 H-Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- AAKDFIEWLESA-NH2 (SEQ ID NO: 30) 32 H-Y-Aib-QGTFTSDYSIYLEK-K(isoGlu-Hexadecanoyl)- AAKEFVEWLLSAGPSSGAPPPS-NH2 (SEQ ID NO: 31) 33 H-Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-isoGlu- Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH2 (SEQ ID NO: 32) 34 H-Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]-isoGlu)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (SEQ ID NO: 33) 35 H-Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (SEQ ID NO: 34) 36 H-Y-Aib-QGTFTSDYSIYLDK-K(eicosanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (SEQ ID NO: 35) 37 H-Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AAKEFVEWLLSAGPSSGAPPPS-NH2 (SEQ ID NO: 36) 38 H-Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]-isoGlu- Peg3-Peg3)-AAKEFVEVVLLSAGPSSGAPPPS-NH2 (SEQ ID NO: 37) 39 H-Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AAKEFIEWLESA-NH2 (SEQ ID NO: 38) 40 H-Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]-isoGlu- Peg3-Peg3)-AAKEFIEWLESA-NH2 (SEQ ID NO: 39) 41 H-Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]-isoGlu- Peg3-Peg3)-AAKEFIEWLESA-NH2 (SEQ ID NO: 40) 42 H-Y-Aib-QGTFTSDYSIALDK-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AQRAFVNWLVA-Aib-KPSSGAPPPS-NH2 (SEQ ID NO: 41) 43 H-Y-Aib-QGTFTSDYSIALDK-K(Octadecanoyl-Dapa-Peg3-Peg3)- AQRAFVNWLVA-Aib-KPSSGAPPPS-NH2 (SEQ ID NO: 42) 44 H-Y-Aib-QGTFTSDYSIALDK-K([19-carboxy-nonadecanoyl]-isoGlu- Peg3-Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS-NH2 (SEQ ID NO: 43) 45 H-Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]-isoGlu- Peg3-Peg3)-AQRAFVEWLLAQK-NH2 (SEQ ID NO: 44) 46 H-Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQK-NH2 (SEQ ID NO: 45) 47 H-Y-Aib-QGTFTSDYSIALEK-K[19-carboxy-nonadecanoyl]-isoGlu-Peg3- Peg3)-AQRAFVEWLLAQK-NH2 (SEQ ID NO: 46) 48 H-Y-Aib-QGTFTSDLSIALEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQK-NH2 (SEQ ID NO: 47) 49 H-Y-Ac4c-QGTFTSDYSIALEK-K([19-carboxy-nonadecanoyl]-isoGlu- Peg3-Peg3)-AQRAFVEWLLAQK-NH2 (SEQ ID NO: 48) 50 H-Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3-Peg3)- AQRAFVEWLLRA-NH2 (SEQ ID NO: 49) 51 H-Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]-isoGlu- Peg3-Peg3)-AQRAFVEWLLRA-NH2 (SEQ ID NO: 50) 52 H-Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl]-isoGlu- Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH2 (SEQ ID NO: 51) - Human GIP Receptor (GIP-R), GLP-1 Receptor (GLP-1-R) and Glucagon Receptor (GCG-R) Activity Assay
- In vitro effects of peptide conjugates of the invention were assessed by measuring the induction of cAMP following stimulation of the respective receptor by glucagon, GIP, GLP1 or analogues of these as outlined in the invention, using the AlphaSceen® cAMP kit from Perkin-Elmer according to instructions. Briefly, HEK293 cells expressing the human GIP R, GLP-1 R or GCG R (stable cell lines generated through transfection of the cDNA for human GIP R, GLP-1 R or GCG R and selection of stable clones) were seeded at 30,000 cells/well in 96-well microtiter plates coated with 0.01% poly-L-lysine, and grown for 1 day in culture in 200 μl growth medium (DMEM, 10% FCS, Penicillin (100 IU/ml), Streptomycin (100 μg/ml)). On the day of analysis, growth medium was removed and the cells were washed once with 150 μl Tyrode's buffer (Tyrode's Salts (9.6 g/I), 10 mM HEPES, pH 7.4). Cells were then incubated in 100 μl Assay buffer (0.1% W/V Alkali-treated Casein and 100 μM IBMX in Tyrode's Buffer) containing increasing concentrations of control and test compounds for 15 min at 370° C. The Assay buffer was removed and cells are lysed in 80 μl Lysis buffer (0.1% w/v BSA, 5 mM HEPES, 0.3% v/v Tween-20) per well. From each well 10 μl of lysed cells were transferred to a 384-well plate and mixed with 15 μl bead-mix (1 Unit/15 μl anti-cAMP Acceptor Beads, 1 Unit/15 μl Donor Beads, and 1 Unit/15 μl Biotinylated cAMP in Assay Buffer). The plates were mixed and incubated in the dark for an hour at room temperature before measuring using an Envision™ plate reader (Perkin-Elmer).
- Results were converted into cAMP concentrations using a cAMP standard curve prepared in KRBH buffer containing 0.1% (v/v) DMSO. The resulting cAMP curves were plotted as absolute cAMP concentrations (nM) over log (test compound concentration) and analyzed using the curve fitting program XLfit.
- Parameters calculated to describe both the potency as well as the agonistic activity of each test compound on the receptors were:
- EC50, a concentration resulting in a half-maximal elevation of cAMP levels, reflecting the potency of the test compound. The results are summarized in Table 2 and Table 2b. The most comprehensive data are summarized in table 2b.
-
TABLE 2 Average EC50 values on the GIP-R, GLP1-R and GCG-R respectively as compared to control peptides. GIP R GLP1 R GCG R Compound (EC50 in nM) (EC50 in nM) (EC50 in nM) hGIP 0.0038 — — Exendin-4 — 0.0043 — glucagon — — 0.010* 1 0.38 0.033 0.013 2 0.35 0.089 0.046 3 0.13 0.015 0.022 5 0.17 0.0092 0.065 6 0.34 0.0095 0.018 7 0.42 0.031 0.086 8 0.20 0.015 0.042 9 0.056 0.0055 0.097 10 0.24 0.012 0.10 11 0.28 0.020 0.11 12 0.084 0.012 0.076 13 0.083 0.0099 0.24 14 0.060 0.013 0.10 15 0.025 0.016 0.058 17 0.091 0.011 0.16 18 0.07 0.021 0.15 19 0.032 0.013 0.024 20 0.047 0.0094 0.057 21 0.18 0.014 0.10 22 0.18 0.028 0.76 23 0.13 0.11 0.14 24 0.10 0.091 0.28 25 0.25 0.28 0.30 26 0.070 0.030 0.040 27 0.12 0.16 0.070 28 0.054 0.058 0.16 29 0.060 0.050 0.15 30 0.15 0.022 0.024 31 0.087 0.013 0.011 32 0.044 0.015 0.15 -
TABLE 2b Average EC050 values on the GIP-R, GLP1-R and GCG-R respectively as compared to control peptides. GIP R GLP1 R GCG R Compound (EC50 in nM) (EC50 in nM) (EC50 in nM) hGIP 0.003 >10 >10 Exendin-4 >10 0.004 >10 glucagon >10 0.48 0.009 1 0.38 0.033 0.013 2 0.35 0.089 0.046 3 0.13 0.015 0.022 5 0.17 0.0092 0.065 6 0.32 0.0095 0.018 7 0.5 0.031 0.086 8 0.2 0.015 0.042 9 0.056 0.0055 0.097 10 0.2 0.012 0.1 11 0.25 0.02 0.11 12 0.084 0.012 0.076 13 0.083 0.0099 0.24 14 0.06 0.013 0.1 15 0.022 0.014 0.058 17 0.091 0.013 0.16 18 0.07 0.021 0.15 19 0.032 0.013 0.024 20 0.047 0.0093 0.057 21 0.18 0.015 0.1 22 0.18 0.03 0.76 23 0.13 0.11 0.14 24 0.097 0.11 0.28 25 0.19 0.28 0.3 26 0.07 0.03 0.04 27 0.099 0.16 0.07 28 0.054 0.058 0.16 29 0.064 0.05 0.15 30 0.15 0.022 0.024 31 0.087 0.013 0.011 32 0.04 0.015 0.15 33 0.0099 0.0093 0.58 34 0.0073 0.0066 0.11 35 0.01 0.012 0.011 37 0.018 NT 0.014 38 0.064 0.015 0.27 39 0.015 0.015 0.013 42 0.0098 0.015 0.032 43 0.0098 0.014 0.036 46 0.011 0.016 0.13 48 0.013 0.013 0.19 51 0.033 0.026 1.4 52 0.016 0.0096 1.8 NT: Not tested - It is anticipated that the exemplified compounds of the invention will have activities at the GCG-R that are close to that of native glucagon. At the same time, it is anticipated that they will exhibit strong GLP-1-R activation with EC50 well below 1 nM. Likewise, it is anticipated that these peptides will also exhibit strong GIP-R activity with and EC50 below or just above 1 nM.
- Pharmacokinetics of Selected Compounds in Mice
- Method
- C57BL/6J mice (males with a body weight of approximately 25 g) were given a single intravenous (i.v.) bolus of each peptide to be tested.
- Following administration of the selected compounds (100 or 200 nmol/kg), blood samples were drawn 0.08, 0.17, 0.5, 1, 4, 8, 16 and 24 hours post-dose. Blood samples were drawn by sublingual bleeding. The dosing vehicle was a phosphate buffer containing mannitol (pH 7.5).
- At each sampling time point, samples from two mice were drawn, i.e. 16 mice were included for each compound. The mice were euthanized immediately after blood sampling by cervical dislocation. Plasma samples were analyzed after solid phase extraction (SPE) or precipitation by liquid chromatography mass spectrometry (LC-MS/MS). Mean plasma concentrations were used for calculation of the pharmacokinetic parameters using the non-compartmental approach in Phoenix WinNonlin 6.3. Plasma terminal elimination half-life (T½) was determined as In(2)/λz where λz is the magnitude of the slope of the log linear regression of the log concentration versus time profile during the terminal phase. The results are summarized in Table 3
-
TABLE 3 Terminal elimination half-life (h) in mice following i.v. administration of selected compounds. Compound T½ (h.) 28 7.8 32 4.1
Claims (36)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/388,328 US20210363213A1 (en) | 2013-11-06 | 2021-07-29 | Glucagon-glp-1-gip triple agonist compounds |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361900933P | 2013-11-06 | 2013-11-06 | |
PCT/EP2014/073971 WO2015067716A1 (en) | 2013-11-06 | 2014-11-06 | Glucagon-glp-1-gip triple agonist compounds |
US201615034784A | 2016-05-05 | 2016-05-05 | |
US16/151,603 US11111285B2 (en) | 2013-11-06 | 2018-10-04 | Glucagon-GLP-1-GIP triple agonist compounds |
US17/388,328 US20210363213A1 (en) | 2013-11-06 | 2021-07-29 | Glucagon-glp-1-gip triple agonist compounds |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/151,603 Continuation US11111285B2 (en) | 2013-11-06 | 2018-10-04 | Glucagon-GLP-1-GIP triple agonist compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20210363213A1 true US20210363213A1 (en) | 2021-11-25 |
Family
ID=51999398
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/034,784 Active US10131702B2 (en) | 2013-11-06 | 2014-11-06 | Glucagon-GLP-1-GIP triple agonist compounds |
US16/151,603 Active US11111285B2 (en) | 2013-11-06 | 2018-10-04 | Glucagon-GLP-1-GIP triple agonist compounds |
US17/388,328 Abandoned US20210363213A1 (en) | 2013-11-06 | 2021-07-29 | Glucagon-glp-1-gip triple agonist compounds |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/034,784 Active US10131702B2 (en) | 2013-11-06 | 2014-11-06 | Glucagon-GLP-1-GIP triple agonist compounds |
US16/151,603 Active US11111285B2 (en) | 2013-11-06 | 2018-10-04 | Glucagon-GLP-1-GIP triple agonist compounds |
Country Status (12)
Country | Link |
---|---|
US (3) | US10131702B2 (en) |
EP (1) | EP3066117B1 (en) |
JP (2) | JP2017503474A (en) |
KR (1) | KR102310392B1 (en) |
CN (1) | CN105829339B (en) |
AU (1) | AU2014345570B2 (en) |
BR (1) | BR112016009995B1 (en) |
CA (1) | CA2929107C (en) |
EA (1) | EA035688B1 (en) |
MX (1) | MX369770B (en) |
TR (1) | TR201902516T4 (en) |
WO (1) | WO2015067716A1 (en) |
Families Citing this family (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA116217C2 (en) | 2012-10-09 | 2018-02-26 | Санофі | Exendin-4 derivatives as dual glp1/glucagon agonists |
AU2013366691A1 (en) | 2012-12-21 | 2015-07-09 | Sanofi | Exendin-4 derivatives |
SI3004155T1 (en) | 2013-05-28 | 2022-02-28 | Takeda Pharmaceutical Company Limited | Peptide compound |
EP3065767B1 (en) | 2013-11-06 | 2020-12-30 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
MX369770B (en) * | 2013-11-06 | 2019-11-21 | Zealand Pharma As | Glucagon-glp-1-gip triple agonist compounds. |
TW201609799A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | Dual GLP-1/GIP receptor agonists |
TW201609796A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | Non-acylated EXENDIN-4 peptide analogues |
TW201609797A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | Dual GLP-1/glucagon receptor agonists |
EP3080150B1 (en) | 2013-12-13 | 2018-08-01 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
TW201625668A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists |
TW201625669A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Peptidic dual GLP-1/glucagon receptor agonists derived from Exendin-4 |
TW201625670A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Dual GLP-1/glucagon receptor agonists derived from EXENDIN-4 |
US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
CA2965732A1 (en) | 2014-10-29 | 2016-05-06 | Zealand Pharma A/S | Gip agonist compounds and methods |
AR105319A1 (en) | 2015-06-05 | 2017-09-27 | Sanofi Sa | PROPHARMS THAT INCLUDE A DUAL AGONIST GLU-1 / GLUCAGON CONJUGATE HIALURONIC ACID CONNECTOR |
WO2016198624A1 (en) | 2015-06-12 | 2016-12-15 | Sanofi | Exendin-4 derivatives as trigonal glp-1/glucagon/gip receptor agonists |
TW201706291A (en) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | New EXENDIN-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists |
TWI622596B (en) | 2015-10-26 | 2018-05-01 | 美國禮來大藥廠 | Glucagon receptor agonists |
JP6995042B2 (en) * | 2016-05-24 | 2022-02-04 | 武田薬品工業株式会社 | Peptide compound |
AR110300A1 (en) * | 2016-12-02 | 2019-03-13 | Sanofi Sa | COMPOUNDS AS TRIGONAL PEPTIDE AGONISTS OF GLP1 / GLUCAGÓN / GIP RECEPTORS |
AR110299A1 (en) | 2016-12-02 | 2019-03-13 | Sanofi Sa | CONJUGATES UNDERSTANDING A DUAL GLP-1 / GLUCAGON AGONIST, A CONNECTOR AND Hyaluronic Acid |
AR110301A1 (en) | 2016-12-02 | 2019-03-13 | Sanofi Sa | COMPOUNDS AS GLP1 / GLUCAGÓN / GIP RECEPTING AGENISTS |
EP3551202B1 (en) | 2016-12-06 | 2024-01-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
JP6563614B1 (en) * | 2016-12-09 | 2019-08-21 | ジーランド・ファーマ・ア/エス | Acylated GLP-1 / GLP-2 dual agonist |
JOP20180028A1 (en) | 2017-03-31 | 2019-01-30 | Takeda Pharmaceuticals Co | Peptide compound |
AR113486A1 (en) * | 2017-12-21 | 2020-05-06 | Lilly Co Eli | INCRETINE ANALOGUES AND ITS USES |
TWI810937B (en) * | 2017-12-21 | 2023-08-01 | 美商美國禮來大藥廠 | Incretin analogs and uses thereof |
US11560402B2 (en) | 2018-04-10 | 2023-01-24 | Sanofi-Aventis Deutschland Gmbh | Method for cleavage of solid phase-bound peptides from the solid phase |
ES2928207T3 (en) | 2018-04-10 | 2022-11-16 | Sanofi Aventis Deutschland | Synthesis of lixisenatide with hooding |
CA3097939A1 (en) | 2018-05-04 | 2019-11-07 | Novo Nordisk A/S | Gip derivatives and uses thereof |
UY38249A (en) | 2018-05-30 | 2019-12-31 | Sanofi Sa | CONJUGATED PRODUCTS INCLUDING A TRIPLE GLP-1 / GLUCAGON / GIP RECEPTOR AGONIST, A CONNECTOR AND HYALURONIC ACID |
JP2022515229A (en) * | 2018-12-21 | 2022-02-17 | ハンミ ファーマシューティカル カンパニー リミテッド | A pharmaceutical composition comprising insulin and a triple active agent having activity on all of glucagon, GLP-1 and GIP receptors. |
JP2022516439A (en) | 2018-12-21 | 2022-02-28 | ジエンス ヘンルイ メデイシンカンパニー リミテッド | Bispecific protein |
PE20221049A1 (en) | 2019-08-19 | 2022-06-30 | Lilly Co Eli | METHODS FOR PREPARING INCRETIN ANALOGS |
CN110684082B (en) * | 2019-10-08 | 2021-12-10 | 江苏诺泰澳赛诺生物制药股份有限公司 | GIP and GLP-1 dual-agonist polypeptide compound, pharmaceutically acceptable salt and application |
PE20221168A1 (en) | 2019-11-11 | 2022-07-25 | Boehringer Ingelheim Int | NPY2 RECEPTOR AGONISTS |
AR120714A1 (en) | 2019-12-18 | 2022-03-09 | Lilly Co Eli | INCRETIN ANALOGS AND THEIR USES |
CN111040022B (en) * | 2019-12-23 | 2021-12-14 | 万新医药科技(苏州)有限公司 | Triplex agonists directed to glucagon-like peptide-1 receptor, glucagon receptor, and pepstatin receptor |
CR20230074A (en) | 2020-08-07 | 2023-04-19 | Boehringer Ingelheim Int | Soluble npy2 receptor agonists |
JP2023537895A (en) * | 2020-08-14 | 2023-09-06 | ハンミ ファーマシューティカル カンパニー リミテッド | Pharmaceutical composition containing triple active long-acting conjugate as an active ingredient |
CA3188884A1 (en) * | 2020-08-14 | 2022-02-17 | Seungjae Baek | Hypotensive pharmaceutical composition comprising triple activator having activity for all of glucagon, glp-1, and gip receptors |
WO2022065898A1 (en) * | 2020-09-25 | 2022-03-31 | 한미약품 주식회사 | Pharmaceutical composition for preventing or treating bone diseases, comprising triple agonist or conjugate thereof having activity with respect to all of glucagon, glp-1 and glp receptors |
CN116583533A (en) * | 2020-10-16 | 2023-08-11 | 韩美药品株式会社 | GIP derivative, long-acting conjugate thereof and pharmaceutical composition comprising the same |
KR20220050821A (en) * | 2020-10-16 | 2022-04-25 | 한미약품 주식회사 | Pharmaceutical composition for preventing or treating vasculitis comprising glucagon/GLP-1/GIP triple agonist or long acting conjugate thereof |
JP2023546088A (en) * | 2020-10-16 | 2023-11-01 | ハンミ ファーマシューティカルズ カンパニー リミテッド | A pharmaceutical composition for the prevention or treatment of lupus-related diseases comprising a glucagon/GLP-1/GIP triple agonist or a long-acting conjugate thereof |
JP2023550594A (en) | 2020-10-30 | 2023-12-04 | ノヴォ ノルディスク アー/エス | GLP-1, GIP, and glucagon receptor triple agonist |
EP4249505A1 (en) | 2020-12-23 | 2023-09-27 | Zhejiang Doer Biologics Co., Ltd. | Long-acting glucagon derivative |
KR20220092442A (en) * | 2020-12-24 | 2022-07-01 | 한미약품 주식회사 | Novel trigonal glucagon/GLP-1/GIP receptor agonist and use thereof |
MX2023008330A (en) | 2021-01-20 | 2024-01-18 | Viking Therapeutics Inc | Compositions and methods for the treatment of metabolic and liver disorders. |
CN117062618A (en) | 2021-05-26 | 2023-11-14 | 联邦生物科技(珠海横琴)有限公司 | Multiple agonists and uses thereof |
CN115572326A (en) * | 2021-06-21 | 2023-01-06 | 广东东阳光药业有限公司 | Triplex agonists of GLP-1, GCG and GIP receptors |
WO2023228156A1 (en) * | 2022-05-27 | 2023-11-30 | D&D Pharmatech Inc. | Peptide compositions and methods of use threof |
WO2024067662A1 (en) * | 2022-09-28 | 2024-04-04 | 广东东阳光药业股份有限公司 | Glp-1/gcg/gip triple-receptor agonist and use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10093713B2 (en) * | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US11111285B2 (en) * | 2013-11-06 | 2021-09-07 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
Family Cites Families (170)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4288627A (en) | 1980-02-12 | 1981-09-08 | Phillips Petroleum Company | Oxidation of thiols employing cobalt molybdate/triethylamine catalyst |
NZ202757A (en) | 1981-12-23 | 1985-11-08 | Novo Industri As | Peptides and medicaments |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
CA2073856C (en) | 1990-01-24 | 2002-12-03 | Douglas I. Buckley | Glp-1 analogs useful for diabetes treatment |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
BR9106435A (en) | 1990-05-09 | 1993-05-04 | Novo Nordisk As | CELLULLASE PREPARATION, ENZYME DEMONSTRATING ANDDOGLUCANASE ACTIVITY, ENDOGLUCANASE ENZYME, DNA CONSTRUCTION, CELL EXPRESSION VECTOR, PROCESS FOR PRODUCING AN ENDOGLUCANASE ENZYME, ADDITIVE DETERGENT COMPOSITION, AND PROCESS TO REDUCE THE RATE AT WHICH CELLULOSE CONTAINING TISSUES BECOME ROUGH, PROVIDE COLOR LIGHTENING OF TISSUES CONTAINING COLORED CELLULOSE, PROVIDES A LOCAL COLOR VARIATION OF TISSUES CONTAINING COLORED, AND IMPROVES PULP DRAINAGE PROPERTIES |
DK36392D0 (en) | 1992-03-19 | 1992-03-19 | Novo Nordisk As | USE OF CHEMICAL COMPOUND |
US5846747A (en) | 1992-03-25 | 1998-12-08 | Novo Nordisk A/S | Method for detecting glucagon-like peptide-1 antagonists and agonists |
DK39892D0 (en) | 1992-03-25 | 1992-03-25 | Bernard Thorens | PEPTIDE |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
WO1995005848A1 (en) | 1993-08-24 | 1995-03-02 | Novo Nordisk A/S | Protracted glp-1 |
KR100429966B1 (en) | 1993-09-07 | 2004-05-04 | 아밀린 파마슈티칼스, 인크. | Composition For Reugulating Gastrointestinal Motility |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
US5523449A (en) | 1995-05-17 | 1996-06-04 | Bayer Corporation | Process for preparing phosphorodichlorido-dithioates by reacting alkylmercaptans with phosphorus trichloride in the presence of sulfur |
ATE316100T1 (en) | 1996-06-05 | 2006-02-15 | Roche Diagnostics Gmbh | EXENDIN ANALOGAS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING SAME |
US6110703A (en) | 1996-07-05 | 2000-08-29 | Novo Nordisk A/S | Method for the production of polypeptides |
CA2262647C (en) | 1996-08-08 | 2007-12-04 | Amylin Pharmaceuticals, Inc. | Methods for regulating gastrointestinal motility |
DE69737479T4 (en) | 1996-08-30 | 2010-05-06 | Novo Nordisk A/S | GLP-1 DERIVATIVES |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6384016B1 (en) | 1998-03-13 | 2002-05-07 | Novo Nordisk A/S | Stabilized aqueous peptide solutions |
US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
DE69732640T2 (en) | 1996-09-09 | 2006-01-12 | Zealand Pharma A/S | SOLID PHASE PEPTIDE SYNTHESIS |
JP2001505872A (en) | 1996-09-09 | 2001-05-08 | ジーランド ファーマシューティカルズ アクティーゼルスカブ | Peptide prodrug containing α-hydroxy acid linker |
UA65549C2 (en) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Use of glucagon-like peptides such as glp-1, glp-1 analog, or glp-1 derivative in methods and compositions for reducing body weight |
WO1998022577A1 (en) | 1996-11-15 | 1998-05-28 | Maria Grazia Masucci | Fusion proteins having increased half-lives |
ES2425559T5 (en) | 1997-01-07 | 2018-02-02 | Amylin Pharmaceuticals, Llc | Pharmaceutical compositions comprising exendins and their agonists |
US6410511B2 (en) | 1997-01-08 | 2002-06-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
US6136784A (en) | 1997-01-08 | 2000-10-24 | Amylin Pharmaceuticals, Inc. | Amylin agonist pharmaceutical compositions containing insulin |
WO1998035033A1 (en) | 1997-02-05 | 1998-08-13 | 1149336 Ontario Inc. | Polynucleotides encoding proexendin, and methods and uses thereof |
US5846937A (en) | 1997-03-03 | 1998-12-08 | 1149336 Ontario Inc. | Method of using exendin and GLP-1 to affect the central nervous system |
CA2289094A1 (en) | 1997-05-07 | 1998-11-12 | Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V., Berlin | New cysteine derivatives, processes for their production, and pharmaceuticals containing them |
PT1019077E (en) | 1997-08-08 | 2008-02-21 | Amylin Pharmaceuticals Inc | Novel exendin agonist compounds |
US7157555B1 (en) | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
US7223725B1 (en) | 1997-11-14 | 2007-05-29 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
DK1032587T4 (en) | 1997-11-14 | 2013-04-08 | Amylin Pharmaceuticals Llc | New exendin agonist compounds |
US7220721B1 (en) | 1997-11-14 | 2007-05-22 | Amylin Pharmaceuticals, Inc. | Exendin agonist peptides |
JP2003522721A (en) | 1997-11-14 | 2003-07-29 | アミリン・ファーマシューティカルズ,インコーポレイテッド | New exendin agonist compounds |
JP2001525371A (en) | 1997-12-05 | 2001-12-11 | イーライ・リリー・アンド・カンパニー | GLP-1 preparation |
US6703359B1 (en) | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
ATE366115T1 (en) | 1998-02-13 | 2007-07-15 | Amylin Pharmaceuticals Inc | INOTROPIC AND DIURETIC EFFECTS OF EXENDIN AND GLP-1 |
AU3247799A (en) | 1998-02-27 | 1999-09-15 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
ATE466028T1 (en) | 1998-02-27 | 2010-05-15 | Novo Nordisk As | N-TERMINALLY MODIFIED GLP-1 DERIVATIVES |
JP4394279B2 (en) | 1998-03-09 | 2010-01-06 | ジーランド ファーマ アクティーゼルスカブ | Pharmacologically active peptide conjugates with reduced propensity to enzymatic hydrolysis |
WO1999049788A1 (en) | 1998-03-30 | 1999-10-07 | Focus Surgery, Inc. | Ablation system |
SE9802080D0 (en) | 1998-06-11 | 1998-06-11 | Hellstroem | Pharmaceutical composition for the treatment of functional dyspepsia and / or irritable bowel syndrome and new use of substances therein |
CA2339326A1 (en) | 1998-08-10 | 2000-02-24 | Josephine Egan | Differentiation of non-insulin producing cells into insulin producing cells by glp-1 or exendin-4 and uses thereof |
WO2000020592A1 (en) | 1998-10-07 | 2000-04-13 | Medical College Of Georgia Research Institute, Inc. | Glucose-dependent insulinotropic peptide for use as an osteotropic hormone |
US6284725B1 (en) | 1998-10-08 | 2001-09-04 | Bionebraska, Inc. | Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue |
EP2322545A1 (en) | 1998-12-07 | 2011-05-18 | Ipsen Pharma | Analogues of GLP-1 |
US7399489B2 (en) | 1999-01-14 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Exendin analog formulations |
CA2356706C (en) | 1999-01-14 | 2014-09-30 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist formulations and methods of administration thereof |
ATE460942T1 (en) | 1999-01-14 | 2010-04-15 | Amylin Pharmaceuticals Inc | EXENDINE FOR GLUCAGON SUPPRESSION |
US6451987B1 (en) | 1999-03-15 | 2002-09-17 | Novo Nordisk A/S | Ion exchange chromatography of proteins and peptides |
US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
EP1956000B1 (en) | 1999-03-17 | 2016-10-05 | Novo Nordisk A/S | Acylating agents useful for acylating peptides |
US6271241B1 (en) | 1999-04-02 | 2001-08-07 | Neurogen Corporation | Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors |
US6924264B1 (en) | 1999-04-30 | 2005-08-02 | Amylin Pharmaceuticals, Inc. | Modified exendins and exendin agonists |
CA2372214A1 (en) | 1999-04-30 | 2000-11-09 | Amylin Pharmaceuticals, Inc. | Modified exendins and exendin agonists |
SI1180121T1 (en) | 1999-05-17 | 2004-04-30 | Conjuchem, Inc. | Long lasting insulinotropic peptides |
US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
US6506724B1 (en) | 1999-06-01 | 2003-01-14 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus |
US6344180B1 (en) | 1999-06-15 | 2002-02-05 | Bionebraska, Inc. | GLP-1 as a diagnostic test to determine β-cell function and the presence of the condition of IGT and type II diabetes |
EP1076066A1 (en) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides for lowering blood glucose levels |
US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
US6586438B2 (en) | 1999-11-03 | 2003-07-01 | Bristol-Myers Squibb Co. | Antidiabetic formulation and method |
US6894024B2 (en) | 2000-10-20 | 2005-05-17 | Amylin Pharmaceuticals, Inc. | Treatment of hibernating myocardium and diabetic cardiomyopathy with a GLP-1 peptide |
GB0121709D0 (en) | 2001-09-07 | 2001-10-31 | Imp College Innovations Ltd | Food inhibition agent |
WO2003053460A1 (en) | 2001-12-19 | 2003-07-03 | Eli Lilly And Company | Crystalline compositions for controlling blood glucose |
EP1545460A4 (en) | 2001-12-20 | 2005-11-16 | Lilly Co Eli | Insulin molecule having protracted time action |
US20030232761A1 (en) | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
EP1837031B1 (en) | 2002-06-07 | 2009-10-14 | Waratah Pharmaceuticals, Inc. | Compositions and methods for treating diabetes |
AU2003243929B2 (en) | 2002-07-04 | 2009-06-04 | Zp Holding Spv K/S | GLP-1 and methods for treating diabetes |
KR20050083713A (en) | 2002-10-02 | 2005-08-26 | 질랜드 파마 에이/에스 | Stabilized exendin-4 compounds |
US7192922B2 (en) | 2002-11-19 | 2007-03-20 | Allegheny-Singer Research Institute | Method of treating left ventricular dysfunction |
GB0300571D0 (en) | 2003-01-10 | 2003-02-12 | Imp College Innovations Ltd | Modification of feeding behaviour |
CA2518776A1 (en) | 2003-04-29 | 2004-11-11 | Eli Lilly And Company | Insulin analogs having protracted time action |
AU2004235872A1 (en) | 2003-05-09 | 2004-11-18 | Novo Nordisk A/S | Peptides for use in treating obesity |
US7623530B2 (en) | 2003-11-20 | 2009-11-24 | Nokia Corporation | Indication of service flow termination by network control to policy decision function |
RU2006131046A (en) | 2004-01-30 | 2008-03-10 | Уэрейта Фармасьютикалз, Инк. (Ca) | JOINT USE OF GLP-1 AGONIST AND GASTRIN COMPOUNDS |
US8076288B2 (en) | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
CA2849552A1 (en) | 2004-02-11 | 2005-08-25 | Amylin Pharmaceuticals, Llc | Hybrid polypeptides with selectable properties |
WO2006051110A2 (en) | 2004-11-12 | 2006-05-18 | Novo Nordisk A/S | Stable formulations of insulinoptropic peptides |
TWI362392B (en) | 2005-03-18 | 2012-04-21 | Novo Nordisk As | Acylated glp-1 compounds |
JP2008539735A (en) | 2005-05-06 | 2008-11-20 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | Glucagon-like peptide 1 (GLP-1) receptor antagonists and methods for their pharmacological use |
JP2008543816A (en) | 2005-06-13 | 2008-12-04 | インペリアル イノベーションズ リミテッド | Novel compounds and their effects on eating behavior |
US20090202497A1 (en) | 2005-08-23 | 2009-08-13 | The General Hospital Corporation | Use of glp-1, glp-1 derivatives or glp-1 fragments for skin regeneration, stimulation of hair growth, or treatment of diabetes |
CN101534846B (en) | 2005-11-07 | 2014-11-05 | 印第安纳大学研究及科技有限公司 | Glucagon analogs exhibiting physiological solubility and stability |
WO2007081824A2 (en) | 2006-01-06 | 2007-07-19 | Case Western Reserve University | Fibrillation resistant proteins |
WO2007095737A1 (en) | 2006-02-21 | 2007-08-30 | Waratah Pharmaceuticals Inc. | Combination therapy for the treatment of diabetes comprising an exendin agonist and a gastrin compound |
WO2007100535A2 (en) | 2006-02-22 | 2007-09-07 | Merck & Co., Inc. | Oxyntomodulin derivatives |
KR101528939B1 (en) | 2006-07-18 | 2015-06-15 | 사노피 | Antagonist antibody against epha2 for the treatment of cancer |
ITMI20061607A1 (en) | 2006-08-09 | 2008-02-10 | Maria Vincenza Carriero | PEPTIDES WITH PHARMACOLOGICAL ACTIVITY |
ES2554773T3 (en) | 2006-10-04 | 2015-12-23 | Case Western Reserve University | Insulin and fibrillation resistant insulin analogues |
JP5819586B2 (en) | 2006-11-08 | 2015-11-24 | ジーランド ファーマ アクティーゼルスカブ | Selective glucagon-like peptide-2 (GLP-2) analogs |
WO2008071010A1 (en) | 2006-12-12 | 2008-06-19 | Waratah Pharmaceuticals Inc. | Combination treatments with selected growth/hormone regulatory factors for diabetes and related diseases |
TWI428346B (en) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | Novel compounds and their effects on feeding behaviour |
US8669228B2 (en) | 2007-01-05 | 2014-03-11 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting enhanced solubility in physiological pH buffers |
AU2008216265B2 (en) | 2007-02-15 | 2014-04-03 | Indiana University Research And Technology Corporation | Glucagon/GLP-1 receptor co-agonists |
EP2025684A1 (en) | 2007-08-15 | 2009-02-18 | Zealand Pharma A/S | Glucagon analogues |
JP5385266B2 (en) | 2007-06-15 | 2014-01-08 | ジーランド ファーマ アクティーゼルスカブ | Glucagon analog |
FR2917552B1 (en) | 2007-06-15 | 2009-08-28 | Sagem Defense Securite | METHOD FOR REGULATING THE TRANSMISSION GEIGE WITHIN A RECEPTION TERMINAL |
EP2679597A1 (en) | 2007-09-05 | 2014-01-01 | Novo Nordisk A/S | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
AU2008326324B9 (en) | 2007-11-20 | 2012-11-15 | Ambrx, Inc. | Modified insulin polypeptides and their uses |
GB2455553B (en) | 2007-12-14 | 2012-10-24 | Nuaire Ltd | Motor mounting assembly for an axial fan |
BRPI0907119A2 (en) | 2008-01-09 | 2015-07-14 | Sanofi Aventis Deutschland | Insulin derivatives having an extremely delayed time action profile |
DE102008003566A1 (en) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | New insulin analogs useful for treating diabetes |
DE102008003568A1 (en) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | New insulin analogs useful for treating diabetes |
MY152979A (en) | 2008-01-09 | 2014-12-15 | Sanofi Aventis Deutschland | Novel insulin derivatives having an extremely delayed time-action profile |
WO2009129250A2 (en) | 2008-04-14 | 2009-10-22 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
RU2010147076A (en) | 2008-04-22 | 2012-05-27 | Кейз Вестерн Ризев Юнивесити (Us) | ANSULIN ANALOGUES SPECIFIC TO ISOFORM |
TWI451876B (en) | 2008-06-13 | 2014-09-11 | Lilly Co Eli | Pegylated insulin lispro compounds |
PE20100255A1 (en) | 2008-06-17 | 2010-04-25 | Univ Indiana Res & Tech Corp | GLUCAGON / GLP-1 RECEPTOR CO-AGONISTS |
TWI474835B (en) * | 2008-06-17 | 2015-03-01 | Univ Indiana Res & Tech Corp | Gip-based mixed agonists for treatment of metabolic disorders and obesity |
CN102088989B (en) | 2008-06-17 | 2014-11-26 | 印第安纳大学研究及科技有限公司 | Glucagon analogs exhibiting enhanced solubility and stability physiological pH buffers |
PL219335B1 (en) | 2008-07-04 | 2015-04-30 | Inst Biotechnologii I Antybiotyków | New slow-release insulin analogues |
MX2011001181A (en) | 2008-07-31 | 2011-04-05 | Univ Case Western Reserve | Halogen-stabilized insulin. |
CN102171244B (en) | 2008-08-07 | 2015-05-13 | 益普生制药股份有限公司 | Analogues of glucose-dependent insulinotropic polypeptide |
CN102149411A (en) | 2008-09-12 | 2011-08-10 | 诺沃—诺迪斯克有限公司 | Method of acylating a peptide or protein |
MX2011006320A (en) | 2008-12-15 | 2011-09-22 | Zealand Pharma As | Glucagon analogues. |
UA104605C2 (en) | 2008-12-15 | 2014-02-25 | Зіленд Фарма А/С | Glucagon analogues |
DK2370462T3 (en) | 2008-12-15 | 2014-09-08 | Zealand Pharma As | Glucagon-ANALOGS |
ES2477880T3 (en) | 2008-12-15 | 2014-07-18 | Zealand Pharma A/S | Glucagon analogues |
JP5789515B2 (en) | 2008-12-19 | 2015-10-07 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションIndiana University Research And Technology Corporation | Insulin analogue |
WO2010080609A1 (en) | 2008-12-19 | 2010-07-15 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
WO2010096052A1 (en) | 2009-02-19 | 2010-08-26 | Merck Sharp & Dohme Corp. | Oxyntomodulin analogs |
WO2010107487A2 (en) | 2009-03-18 | 2010-09-23 | Wu Nian | Lipid-drug conjugates for drug delivery |
CN101519446A (en) | 2009-03-31 | 2009-09-02 | 上海一就生物医药有限公司 | Method for preparing recombinant human insulin and analogs of recombinant human insulin |
AU2010260058B2 (en) | 2009-06-16 | 2015-09-24 | Indiana University Research And Technology Corporation | GIP receptor-active glucagon compounds |
DK2454282T3 (en) | 2009-07-13 | 2015-05-04 | Zealand Pharma As | acetylated glucagonanaloger |
DK2513140T3 (en) | 2009-12-16 | 2016-01-18 | Novo Nordisk As | Double-acylated GLP-1 derivatives |
US20110312881A1 (en) | 2009-12-21 | 2011-12-22 | Amunix, Inc. | Bifunctional polypeptide compositions and methods for treatment of metabolic and cardiovascular diseases |
MX342409B (en) * | 2010-01-20 | 2016-09-28 | Zealand Pharma As | Treatment of cardiac conditions. |
CA2788304A1 (en) | 2010-01-27 | 2011-08-04 | Indiana University Research And Technology Corporation | Glucagon antagonist - gip agonist conjugates and compositions for the treatment of metabolic disorders and obesity |
AR080592A1 (en) | 2010-03-26 | 2012-04-18 | Lilly Co Eli | PEPTIDE WITH ACTIVITY FOR GIP-R AND GLP-1-R, FAMILY FORMULATION THAT UNDERSTANDS IT, ITS USE TO PREPARE A USEFUL MEDICINAL PRODUCT FOR THE TREATMENT OF MELLITUS DIABETES AND TO INDICATE WEIGHT LOSS |
EP2552951A1 (en) | 2010-03-26 | 2013-02-06 | Novo Nordisk A/S | Novel glucagon analogues |
EP2552952A1 (en) | 2010-03-26 | 2013-02-06 | Novo Nordisk A/S | Novel glucagon analogues |
SG184988A1 (en) | 2010-04-27 | 2012-11-29 | Zealand Pharma As | Peptide conjugates of glp-1 receptor agonists and gastrin and their use |
AU2011247824B2 (en) | 2010-04-27 | 2014-02-13 | Betta Pharmaceuticals Co., Ltd | Glucagon-like peptide-1 analogue and use thereof |
UY33462A (en) | 2010-06-23 | 2012-01-31 | Zealand Pharma As | GLUCAGON ANALOGS |
WO2011160633A1 (en) | 2010-06-24 | 2011-12-29 | Zealand Pharma A/S | Glucagon analogues |
EP2637699B1 (en) | 2010-11-09 | 2018-05-16 | Novo Nordisk A/S | Double-acylated glp-1 derivatives with a linker |
EP2665487A1 (en) | 2011-01-20 | 2013-11-27 | Zealand Pharma A/S | Combination of acylated glucagon analogues with insulin analogues |
AU2012234276A1 (en) | 2011-03-28 | 2013-08-29 | Novo Nordisk A/S | Novel glucagon analogues |
WO2012138941A1 (en) | 2011-04-05 | 2012-10-11 | Longevity Biotech, Inc. | Compositions comprising glucagon analogs and methods of making and using the same |
MX355361B (en) | 2011-04-12 | 2018-04-17 | Novo Nordisk As | Double-acylated glp-1 derivatives. |
WO2012150503A2 (en) * | 2011-05-03 | 2012-11-08 | Zealand Pharma A/S | Glu-glp-1 dual agonist signaling-selective compounds |
WO2012153196A2 (en) | 2011-05-10 | 2012-11-15 | Zealand Pharma A/S | Glu-glp-1 dual agonist signaling-selective compounds |
JP5914641B2 (en) | 2011-06-10 | 2016-05-11 | ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッドBeijing Hanmi Pharmaceutical Co., Ltd. | Glucose-dependent insulinotropic polypeptide analogs, pharmaceutical compositions and uses thereof |
JP6352806B2 (en) | 2011-09-23 | 2018-07-04 | ノヴォ ノルディスク アー/エス | New glucagon analogues |
BR112014010780A2 (en) | 2011-11-03 | 2017-04-25 | Zealand Pharma As | glp-1-gastrin receptor agonist peptide conjugates |
PE20142113A1 (en) | 2011-12-23 | 2014-12-03 | Zealand Pharma As | GLUCAGON ANALOGS |
KR20150006052A (en) | 2012-05-03 | 2015-01-15 | 질랜드 파마 에이/에스 | Glucagon-like-peptide-2 (glp-2) analogues |
MX356641B (en) | 2012-05-03 | 2018-06-07 | Zealand Pharma As | Gip-glp-1 dual agonist compounds and methods. |
AR091476A1 (en) | 2012-06-21 | 2015-02-04 | Univ Indiana Res & Tech Corp | REGION FUSION POLYPEPTIDES Fc POLYPEPTIDE BINDING RECEIVER OF INCRETINA AND CONJUGADOS WITH EFECTIVE FUNCTION Fc ALTERED |
NZ704043A (en) | 2012-07-23 | 2017-07-28 | Zealand Pharma As | Glucagon analogues |
TWI608013B (en) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | Glucagon analogues |
AU2013366691A1 (en) | 2012-12-21 | 2015-07-09 | Sanofi | Exendin-4 derivatives |
WO2014140222A1 (en) * | 2013-03-14 | 2014-09-18 | Medimmune Limited | Pegylated glucagon and glp-1 co-agonists for the treatment of obesity |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
PL3057984T3 (en) | 2013-10-17 | 2018-12-31 | Zealand Pharma A/S | Acylated glucagon analogues |
TW201609796A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | Non-acylated EXENDIN-4 peptide analogues |
CN106029088A (en) | 2014-02-18 | 2016-10-12 | 诺和诺德股份有限公司 | Stable glucagon analogues and use for treatment of hypoglycaemia |
CA2965732A1 (en) | 2014-10-29 | 2016-05-06 | Zealand Pharma A/S | Gip agonist compounds and methods |
JP6989385B2 (en) | 2015-04-16 | 2022-01-05 | ジーランド ファーマ アクティーゼルスカブ | Acylated glucagon analog |
-
2014
- 2014-11-06 MX MX2016005560A patent/MX369770B/en active IP Right Grant
- 2014-11-06 CN CN201480061187.4A patent/CN105829339B/en active Active
- 2014-11-06 WO PCT/EP2014/073971 patent/WO2015067716A1/en active Application Filing
- 2014-11-06 TR TR2019/02516T patent/TR201902516T4/en unknown
- 2014-11-06 EA EA201690629A patent/EA035688B1/en not_active IP Right Cessation
- 2014-11-06 CA CA2929107A patent/CA2929107C/en active Active
- 2014-11-06 AU AU2014345570A patent/AU2014345570B2/en active Active
- 2014-11-06 US US15/034,784 patent/US10131702B2/en active Active
- 2014-11-06 JP JP2016527192A patent/JP2017503474A/en not_active Withdrawn
- 2014-11-06 EP EP14805199.8A patent/EP3066117B1/en active Active
- 2014-11-06 BR BR112016009995-8A patent/BR112016009995B1/en active IP Right Grant
- 2014-11-06 KR KR1020167014989A patent/KR102310392B1/en active IP Right Grant
-
2018
- 2018-10-04 US US16/151,603 patent/US11111285B2/en active Active
-
2019
- 2019-12-06 JP JP2019221419A patent/JP2020045362A/en active Pending
-
2021
- 2021-07-29 US US17/388,328 patent/US20210363213A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10093713B2 (en) * | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US11008375B2 (en) * | 2013-11-06 | 2021-05-18 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US11111285B2 (en) * | 2013-11-06 | 2021-09-07 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
Also Published As
Publication number | Publication date |
---|---|
MX2016005560A (en) | 2016-11-15 |
EA201690629A1 (en) | 2016-10-31 |
AU2014345570B2 (en) | 2019-01-24 |
US10131702B2 (en) | 2018-11-20 |
CA2929107C (en) | 2023-09-26 |
AU2014345570A1 (en) | 2016-05-12 |
MX369770B (en) | 2019-11-21 |
KR102310392B1 (en) | 2021-10-13 |
TR201902516T4 (en) | 2019-03-21 |
US11111285B2 (en) | 2021-09-07 |
CA2929107A1 (en) | 2015-05-14 |
KR20160074008A (en) | 2016-06-27 |
CN105829339A (en) | 2016-08-03 |
EA035688B1 (en) | 2020-07-27 |
BR112016009995A2 (en) | 2017-12-05 |
EP3066117B1 (en) | 2019-01-02 |
WO2015067716A1 (en) | 2015-05-14 |
EP3066117A1 (en) | 2016-09-14 |
US20160257729A1 (en) | 2016-09-08 |
CN105829339B (en) | 2021-03-12 |
JP2020045362A (en) | 2020-03-26 |
JP2017503474A (en) | 2017-02-02 |
US20190270789A1 (en) | 2019-09-05 |
BR112016009995B1 (en) | 2023-04-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11111285B2 (en) | Glucagon-GLP-1-GIP triple agonist compounds | |
US11008375B2 (en) | GIP-GLP-1 dual agonist compounds and methods | |
US11814417B2 (en) | GIP agonist compounds and methods | |
AU2014345569A1 (en) | GIP-GLP-1 dual agonist compounds and methods |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: APPLICATION UNDERGOING PREEXAM PROCESSING |
|
AS | Assignment |
Owner name: ZOOLANDER SA LLC, NEW YORK Free format text: PATENT SECURITY AGREEMENT;ASSIGNOR:ZEALAND PHARMA A/S;REEL/FRAME:058593/0261 Effective date: 20211213 |
|
AS | Assignment |
Owner name: ZEALAND PHARMA A/S, DENMARK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JUST, RASMUS;RIBER, DITTE;SHELTON, ANNE PERNILLE TOFTENG;AND OTHERS;SIGNING DATES FROM 20150211 TO 20160216;REEL/FRAME:059037/0522 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
AS | Assignment |
Owner name: ZEALAND PHARMA A/S, DENMARK Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:ZOOLANDER SA LLC;REEL/FRAME:063624/0547 Effective date: 20230509 |
|
AS | Assignment |
Owner name: ZEALAND PHARMA A/S, DENMARK Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:ZOOLANDER SA LLC;REEL/FRAME:063672/0342 Effective date: 20230509 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |