JP7239566B2 - グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 - Google Patents
グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 Download PDFInfo
- Publication number
- JP7239566B2 JP7239566B2 JP2020516667A JP2020516667A JP7239566B2 JP 7239566 B2 JP7239566 B2 JP 7239566B2 JP 2020516667 A JP2020516667 A JP 2020516667A JP 2020516667 A JP2020516667 A JP 2020516667A JP 7239566 B2 JP7239566 B2 JP 7239566B2
- Authority
- JP
- Japan
- Prior art keywords
- glp1
- disease
- antigen
- pharmaceutical composition
- glp1 receptor
- 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.)
- Active
Links
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title description 84
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 claims description 93
- 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 claims description 92
- 102100040918 Pro-glucagon Human genes 0.000 claims description 88
- 239000012634 fragment Substances 0.000 claims description 64
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims description 50
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 claims description 50
- 239000000427 antigen Substances 0.000 claims description 48
- 102000036639 antigens Human genes 0.000 claims description 47
- 108091007433 antigens Proteins 0.000 claims description 47
- 108020001507 fusion proteins Proteins 0.000 claims description 47
- 102000037865 fusion proteins Human genes 0.000 claims description 47
- 230000027455 binding Effects 0.000 claims description 45
- 210000004369 blood Anatomy 0.000 claims description 42
- 239000008280 blood Substances 0.000 claims description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
- 206010012601 diabetes mellitus Diseases 0.000 claims description 33
- 150000001413 amino acids Chemical group 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 31
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims description 27
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims description 27
- 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 claims description 26
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 230000004048 modification Effects 0.000 claims description 18
- 238000012986 modification Methods 0.000 claims description 18
- 208000024891 symptom Diseases 0.000 claims description 18
- 208000008589 Obesity Diseases 0.000 claims description 17
- 235000020824 obesity Nutrition 0.000 claims description 17
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 14
- 102000004877 Insulin Human genes 0.000 claims description 11
- 108090001061 Insulin Proteins 0.000 claims description 11
- 208000006011 Stroke Diseases 0.000 claims description 11
- 229940125396 insulin Drugs 0.000 claims description 11
- 108091033319 polynucleotide Proteins 0.000 claims description 11
- 102000040430 polynucleotide Human genes 0.000 claims description 11
- 239000002157 polynucleotide Substances 0.000 claims description 11
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 9
- 229960003105 metformin Drugs 0.000 claims description 9
- 238000002560 therapeutic procedure Methods 0.000 claims description 9
- 208000019622 heart disease Diseases 0.000 claims description 8
- 208000017169 kidney disease Diseases 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
- 239000013598 vector Substances 0.000 claims description 6
- 102000035195 Peptidases Human genes 0.000 claims description 5
- 108091005804 Peptidases Proteins 0.000 claims description 5
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 5
- 229960002802 bromocriptine Drugs 0.000 claims description 5
- 229960000698 nateglinide Drugs 0.000 claims description 5
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims description 5
- 229960004034 sitagliptin Drugs 0.000 claims description 5
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 5
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940123208 Biguanide Drugs 0.000 claims description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 208000028389 Nerve injury Diseases 0.000 claims description 4
- 239000004365 Protease Substances 0.000 claims description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims description 4
- 229940100389 Sulfonylurea Drugs 0.000 claims description 4
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 4
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 4
- 239000002220 antihypertensive agent Substances 0.000 claims description 4
- 229940030600 antihypertensive agent Drugs 0.000 claims description 4
- 235000015872 dietary supplement Nutrition 0.000 claims description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 4
- 230000008764 nerve damage Effects 0.000 claims description 4
- 229960003611 pramlintide Drugs 0.000 claims description 4
- 108010029667 pramlintide Proteins 0.000 claims description 4
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
- 208000001280 Prediabetic State Diseases 0.000 claims description 3
- 206010043458 Thirst Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 206010047513 Vision blurred Diseases 0.000 claims description 3
- 206010049040 Weight fluctuation Diseases 0.000 claims description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 235000005911 diet Nutrition 0.000 claims description 3
- 230000037213 diet Effects 0.000 claims description 3
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000004064 dysfunction Effects 0.000 claims description 3
- 208000030533 eye disease Diseases 0.000 claims description 3
- 206010016256 fatigue Diseases 0.000 claims description 3
- 208000010706 fatty liver disease Diseases 0.000 claims description 3
- 230000010030 glucose lowering effect Effects 0.000 claims description 3
- 230000035876 healing Effects 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 230000027939 micturition Effects 0.000 claims description 3
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 3
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 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(=O)NCC(O)=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 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 claims description 3
- 230000000241 respiratory effect Effects 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000004026 insulin derivative Substances 0.000 claims description 2
- 230000006337 proteolytic cleavage Effects 0.000 claims description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 claims 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims 1
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims 1
- 208000024693 gingival disease Diseases 0.000 claims 1
- 229940043266 rosin Drugs 0.000 claims 1
- 230000008961 swelling Effects 0.000 claims 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 125
- 108090000765 processed proteins & peptides Proteins 0.000 description 57
- 102000025171 antigen binding proteins Human genes 0.000 description 47
- 108091000831 antigen binding proteins Proteins 0.000 description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 47
- 238000000034 method Methods 0.000 description 44
- 235000018102 proteins Nutrition 0.000 description 41
- 102000004169 proteins and genes Human genes 0.000 description 41
- 108090000623 proteins and genes Proteins 0.000 description 41
- 235000001014 amino acid Nutrition 0.000 description 37
- 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 description 34
- 239000008103 glucose Substances 0.000 description 34
- 125000003275 alpha amino acid group Chemical group 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 30
- 102000004196 processed proteins & peptides Human genes 0.000 description 27
- 201000010099 disease Diseases 0.000 description 26
- 230000000694 effects Effects 0.000 description 23
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 22
- 208000035475 disorder Diseases 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 238000006467 substitution reaction Methods 0.000 description 20
- 108060003951 Immunoglobulin Proteins 0.000 description 17
- 102000018358 immunoglobulin Human genes 0.000 description 17
- 229920001184 polypeptide Polymers 0.000 description 15
- 238000003776 cleavage reaction Methods 0.000 description 14
- 230000007017 scission Effects 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 11
- 238000012217 deletion Methods 0.000 description 11
- 230000037430 deletion Effects 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 108020004707 nucleic acids Proteins 0.000 description 10
- 102000039446 nucleic acids Human genes 0.000 description 10
- 150000007523 nucleic acids Chemical class 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 238000007792 addition Methods 0.000 description 9
- 238000003556 assay Methods 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 201000001421 hyperglycemia Diseases 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- -1 metformin) Chemical class 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000029087 digestion Effects 0.000 description 5
- 230000002641 glycemic effect Effects 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 238000004885 tandem mass spectrometry Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 4
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 4
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 4
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 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 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 238000011577 humanized mouse model Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000000813 peptide hormone Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 3
- 108060003199 Glucagon Proteins 0.000 description 3
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 3
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 3
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010033307 Overweight Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 229960001713 canagliflozin Drugs 0.000 description 3
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 108010005794 dulaglutide Proteins 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 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 description 3
- 229960004666 glucagon Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 3
- 238000002170 nanoflow liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 2
- AXAVXPMQTGXXJZ-UHFFFAOYSA-N 2-aminoacetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(O)=O.OCC(N)(CO)CO AXAVXPMQTGXXJZ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 229960002632 acarbose Drugs 0.000 description 2
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 238000011360 adjunctive therapy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000002820 assay format Methods 0.000 description 2
- 229940090047 auto-injector Drugs 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 150000004283 biguanides Chemical class 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 238000001360 collision-induced dissociation Methods 0.000 description 2
- 235000001434 dietary modification Nutrition 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 229960005175 dulaglutide Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003158 enteroendocrine cell Anatomy 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- OXZOLXJZTSUDOM-UHFFFAOYSA-N fluoro 2,2,2-trifluoroacetate Chemical compound FOC(=O)C(F)(F)F OXZOLXJZTSUDOM-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 102000045598 human DPP4 Human genes 0.000 description 2
- 102000056448 human GLP1R Human genes 0.000 description 2
- 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 2
- 239000000859 incretin Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000009707 neogenesis Effects 0.000 description 2
- 230000001019 normoglycemic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 208000030613 peripheral artery disease Diseases 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- ORMNNUPLFAPCFD-DVLYDCSHSA-M phenethicillin potassium Chemical compound [K+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C(C)OC1=CC=CC=C1 ORMNNUPLFAPCFD-DVLYDCSHSA-M 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 230000036186 satiety Effects 0.000 description 2
- 235000019627 satiety Nutrition 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 150000001467 thiazolidinediones Chemical class 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BEJKOYIMCGMNRB-GRHHLOCNSA-N (2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BEJKOYIMCGMNRB-GRHHLOCNSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 101100338242 Drosophila virilis His1.1 gene Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108010090549 Endothelin A Receptor Proteins 0.000 description 1
- 102100040630 Endothelin-1 receptor Human genes 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide 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(N)=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 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000877314 Homo sapiens Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 1
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 description 1
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 description 1
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 description 1
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 description 1
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102100022964 Immunoglobulin kappa variable 3-20 Human genes 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 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
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- 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 1
- 238000012491 Luciferase Bioassay Methods 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100395023 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) his-7 gene Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 235000016496 Panda oleosa Nutrition 0.000 description 1
- 240000000220 Panda oleosa Species 0.000 description 1
- 241000577979 Peromyscus spicilegus Species 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 241000219492 Quercus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960004733 albiglutide Drugs 0.000 description 1
- OGWAVGNOAMXIIM-UHFFFAOYSA-N albiglutide Chemical compound O=C(O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)CNC(=O)C(N)CC=1(N=CNC=1))CCC(=O)O)C(O)C)CC2(=CC=CC=C2))C(O)C)CO)CC(=O)O)C(C)C)CO)CO)CC3(=CC=C(O)C=C3))CC(C)C)CCC(=O)O)CCC(=O)N)C)C)CCCCN)CCC(=O)O)CC4(=CC=CC=C4))C(CC)C)C)CC=6(C5(=C(C=CC=C5)NC=6)))CC(C)C)C(C)C)CCCCN)CCCNC(=N)N OGWAVGNOAMXIIM-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 238000003981 capillary liquid chromatography Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000006806 disease prevention Effects 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
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229940015979 epipen Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 239000011536 extraction buffer Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000002546 full scan Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 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
- 229940062714 humalog mix Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 238000000111 isothermal titration calorimetry Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000011542 limb amputation Methods 0.000 description 1
- 229960002397 linagliptin Drugs 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 108700027806 rGLP-1 Proteins 0.000 description 1
- 238000004725 rapid separation liquid chromatography Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
- C07K16/082—Hepadnaviridae, e.g. hepatitis B virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Child & Adolescent Psychology (AREA)
- Neurology (AREA)
- Toxicology (AREA)
- Communicable Diseases (AREA)
Description
「グルカゴン様ペプチド1」とも呼ばれる用語「GLP1」は、栄養摂取後に腸管L細胞から放出される31アミノ酸のペプチドホルモンを指す。GLP1はGLP1受容体と結合し、膵臓β細胞からのグルコース応答性インスリン分泌を増強し、インスリン発現を増加させ、β細胞アポトーシスを阻害し、β細胞新生を促進し、グルカゴン分泌を低減し、胃内消化時間を遅延し、飽満を促進し、末梢グルコース処理能を増大させる。特定実施形態では、用語「GLP1」は、完全長GLP1ペプチド(配列番号3)のアミノ酸7~37を含む、成熟型31アミノ酸のペプチドホルモン(配列番号4)を指す。この用語はGLP1の変異体も含み、これらの変異体は1、2、3、4、5または6個のアミノ酸置換、付加または欠失を含む。例えばこの用語は、配列番号5、6、7、または8のアミノ酸配列を含む変異体を含む。
本発明のGLP1受容体アゴニストは、記載したGLP1受容体アゴニストのアミノ酸配列と異なるアミノ酸配列を有するが、GLP1受容体と結合する能力は保持するタンパク質を包含する。このような変異体GLP1受容体アゴニストは、親配列と比較したときアミノ酸の1つまたはそれ以上の付加、欠失、または置換を含むが、記載したGLP1受容体アゴニストのそれとほぼ等しい生物活性を示す。同様に、本発明のGLP1受容体アゴニストコードDNA配列は、開示配列と比較したときヌクレオチドの1つまたはそれ以上の付加、欠失、または置換を含むが、本発明のGLP1受容体アゴニストと生物学的にほぼ同等であるGLP1受容体アゴニストをコードする配列を包含する。
一般に、本発明のGLP1受容体アゴニストはGLP1受容体と結合することによって機能し、結合時にGLP1受容体の活性化を助長する。特定実施形態では、本発明のタンパク質はGLP1受容体と高いアフィニティーで結合する。例えば本発明は、例えば本明細書中の実施例2中で定義したアッセイ形式を使用し、ルシフェラーゼアッセイにより測定して(例えば、25℃または37℃で)GLP1受容体の活性化をもたらすGLP1受容体アゴニストを含む。特定実施形態では、GLP1受容体アゴニストは、例えば本明細書中の実施例2中で定義したアッセイ形式、または実質的に類似したアッセイを使用し、ルシフェラーゼアッセイにより測定して10nM未満、500pM未満、または250pM未満のEC50でGLP1受容体を活性化する。
本発明は、本発明のGLP1受容体アゴニストを含む治療用組成物を提供する。本発明による治療用組成物を、製剤中に取り込まれた適切な担体、賦形剤、および他の作用物質と共に投与して、改善された移動性、送達性、耐性などをもたらす。多数の適切な製剤を、全ての製薬化学者に知られている処方集:Remington’s Pharmaceutical Sciences、Mack Publishing Company、Easton、PA中に見ることができる。これらの製剤は、例えば粉末、ペースト、軟膏、ゼリー、ワックス、油、脂質、(カチオン性またはアニオン性)脂質含有小胞(LIPOFECTIN(商標)など)、DNAコンジュゲート、無水吸収性ペースト、水中油型および油中水型エマルション、エマルションカルボワックス(様々な分子量のポリエチレングリコール)、半固形ゲル、およびカルボワックス含有半固形混合物を含む。Powellら、「Compendium of excipients for parenteral formulations」PDA(1998年)J Pharm Sci Technol52:238~311頁も参照。
本発明のGLP1受容体アゴニストは、糖尿病などの高血糖症と関係がある疾患もしくは障害もしくは状態の治療、および/または予防、および/またはこのような疾患、障害もしくは状態と関係がある少なくとも1つの症状の軽減に有用である。一実施形態では、本発明のGLP1受容体アゴニストを、糖尿病(例えば、2型糖尿病)がある患者に治療用量で投与することができる。
併用療法剤は、本発明のGLP1受容体アゴニスト、および本発明のGLP1受容体アゴニスト、またはその本発明の生物活性断片と有利に併用することができる任意の他の治療剤を含むことができる。本発明のGLP1受容体アゴニストは、高血糖症(例えば糖尿病)と関係がある任意の疾患または障害を治療するのに使用される1つまたはそれ以上の薬物または治療剤と相乗的に併用することができる。幾つかの実施形態では、本発明のGLP1受容体アゴニストを第2の治療剤と併用して、対象における血糖レベルを低減することができ、または糖尿病の1つまたはそれ以上の症状を軽減することができる。
特定実施形態に従い、一回用量の本発明のGLP1受容体アゴニスト(またはGLP1受容体アゴニストと本明細書で言及する任意の他の治療活性成分の組合せを含む医薬組成物)を、それを必要とする対象に投与することができる。本発明の特定実施形態に従い、複数用量の本発明のGLP1受容体アゴニスト(またはGLP1受容体アゴニストと本明細書で言及する任意の他の治療活性成分の組合せを含む医薬組成物)を、規定の時間行程にわたり対象に投与することができる。本発明のこの態様に従う方法は、複数用量の本発明のGLP1受容体アゴニストを対象に逐次的に投与する工程を含む。本明細書中で使用する「逐次的に投与する」は、異なる時間地点で、例えば所定間隔(例えば数時間、数日間、数週間または数カ月)隔てた異なる日に、各用量のGLP1受容体アゴニストを対象に投与することを意味する。本発明は、1回の初回用量のGLP1受容体アゴニスト、次に1回またはそれ以上の二次用量のGLP1受容体アゴニスト、および場合により次に1回またはそれ以上の三次用量のGLP1受容体アゴニストを患者に逐次的に投与する工程を含む方法を含む。
本発明の方法に従い対象に投与されるGLP1受容体アゴニストの量は、一般に治療有効量である。本明細書中で使用する語句「治療有効量」は、(a)正常レベル(例えば、80~130mg/dLの食前血中グルコースレベル)への高血糖レベルの低減、および/または(b)糖尿病の1つまたはそれ以上の症状または徴候の検出可能な改善の、1つまたはそれ以上をもたらすGLP1受容体アゴニストの量を意味する。
実施形態1では、本発明は、(i)N末端へのアミノ酸の付加、および(ii)ペプチド配列からのアミノ酸の欠失からなる群から選択される少なくとも1つのアミノ酸修飾がある成熟GLP1(7~37)(配列番号4)を含むグルカゴン様ペプチド1(GLP1)変異体であって、タンパク質分解切断に対する高い耐性および/または高い血中グルコース低下能力を有するGLP1変異体を提供する。
酵素ジペプチジルペプチダーゼ4(DPP4)によるその急速な不活性化のため、GLP1(7~37)は非常に短い循環半減期(1~2分)を有する。以前の研究は、GLP1(7~37)の位置8における様々なアミノ酸置換によってDPP4に対する耐性が高まり、それによってさらに長い半減期をもたらすことを示した(Deaconら、1998年、Diabetologia41:271~278頁)。しかしながら、これらの分子のDPP4切断に対する感受性は残る。したがって、DPP4に対してより一層の耐性がある、新たな分子を開発する必要がある。
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(配列番号4)を有する。
・アミノ酸配列HEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(配列番号5)を含むDes-Ala-GLP1
・アミノ酸配列QHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(配列番号6)を含むQ-GLP1
・アミノ酸配列AHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(配列番号7)を含むA-GLP1
・アミノ酸配列AEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(配列番号8)を含むdesH-GLP1
・mAb1の軽鎖のN末端と融合したDes-Ala-GLP1-mAb1:Des-Ala-GLP1(配列番号5)
・mAb1の軽鎖のN末端と融合したQ-GLP1-mAb1:Q-GLP1(配列番号6)
・mAb1の軽鎖のN末端と融合したA-GLP1-mAb1:A-GLP1(配列番号7)
・GLP1-hFc(配列番号9)
・A-GLP1-hFc(配列番号10)
・Q-GLP1-hFc(配列番号11)
・Des-Ala-GLP1-hFc(配列番号12)
・desH-GLP1-hFc(配列番号13)
コンパレーター:Glaesnerら、2010年(Diabetes Metab.Res.Rev.26:287~296頁)中に開示された、hIgG4Fcドメインと融合したLY2189265のアミノ酸配列特性を有するGLP1アナログ(デュラグルチド;Eli Lilly)を、以下の実施例中でコンパレーター(配列番号14)として使用した。
cAMPに応答するcreプロモーターの制御下でヒトGLP1受容体およびルシフェラーゼコード配列を安定的に発現するレポーター細胞株293/FSC11/Cre-Lucにおいて、cAMP生成を刺激するそれらの能力に関してGLP1融合タンパク質を試験した。
血中グルコースおよびグルコース抵抗性に対する抗GLP1R抗体の軽鎖のN末端と融合したQ-GLP1(Q-GLP1-mAb1)の影響を、ヒトGLP1Rタンパク質を発現する遺伝子操作型マウス(「GLP1Rヒト化マウス」)において決定した。31匹のGLP1Rヒト化マウスを、7~8匹の動物の4群に分けた。各群に、194nmol/kgでアイソタイプ対照、Q-GLP1-hFc、mAb1、またはQ-GLP1-mAb1を一回皮下注射した。マウスは第0、1、4、7、11、14、16、18日に飼育状態で出血させ、第22日に血中グルコースを測定した。各時間地点での血中グルコースレベルの平均±SEMを各群に関して計算し、それを表2中に示す。
様々なGLP1変異体および融合タンパク質の安定性を、血中プロテアーゼとそれらをインキュベートし、質量分析によって切断ペプチドを分析することにより試験した。
血清酵素による切断に対する各構築物の感受性を特徴付けるため、各構築物に関して完全ペプチド(N末端ペプチド)、切断ペプチド(切断後のN末端ペプチド)、および1つの内部参照ペプチド(構築物における如何なる修飾にも影響を受けない安定ペプチド)をナノLC-MS/MSによってモニタリングした。完全ペプチドと参照ペプチドの低減した比、および切断ペプチドと参照ペプチドの付随的に増大した比は、経時的な構築物の酵素媒介切断を示唆した。以下の式:100×切断ペプチドの面積/(切断ペプチドの面積+非切断ペプチドの面積)を使用して切断率を計算した。
Claims (14)
- 配列番号6のアミノ酸配列からなるグルカゴン様ペプチド1(GLP1)変異体;およびGLP1受容体と特異的に結合し、軽鎖可変領域(LCVR)と重鎖可変領域(HCVR)を含む抗体またはその抗原結合性断片である安定型ドメインを含む融合タンパク質であって、ジペプチジルペプチダーゼ4(DPP4)および血中プロテアーゼによるタンパク質分解切断に対する高い耐性および/または高い血中グルコース低下能力を有する、前記融合タンパク質。
- GLP1変異体が前記抗体またはその抗原結合性断片のHCVRのN末端またはC末端と融合した、請求項1に記載の融合タンパク質。
- GLP1変異体が前記抗体またはその抗原結合性断片のLCVRのN末端またはC末端と融合した、請求項1に記載の融合タンパク質。
- 請求項1~3のいずれか1項に記載の融合タンパク質および薬学的に許容される担体または希釈剤を含む医薬組成物。
- 請求項1~3のいずれか1項に記載の融合タンパク質をコードするポリヌクレオチド配列を含む単離ポリヌクレオチド分子。
- 請求項5に記載のポリヌクレオチド分子を含むベクター。
- 請求項6に記載のベクター内のポリヌクレオチド分子によりコードされる融合タンパク質を発現する細胞。
- 対象において血糖レベルを低減するために使用するための、請求項4に記載の医薬組成物。
- 対象が、糖尿病、肥満症、インスリン抵抗性、高血圧、脂質異常症、2型糖尿病、1型
糖尿病、前糖尿病、心血管疾患、アテローム性動脈硬化症、うっ血性心不全、冠動脈性心疾患、動脈硬化症、末梢動脈疾患、脳卒中、呼吸機能障害、腎疾患、脂肪肝疾患、非アルコール性脂肪性肝炎(NASH)、およびメタボリックシンドロームからなる群から選択される疾患または障害を有する、請求項8に記載の医薬組成物。 - 2型糖尿病の少なくとも1つの症状、兆候または合併症を予防、治療または軽減するために使用するための、請求項4に記載の医薬組成物。
- 少なくとも1つの症状、徴候または合併症が、高血糖レベル、過剰な喉の渇き、頻尿、尿中ケトン体の存在、疲労、体重変動、かすみ目、治癒が遅い痛み、頻繁な感染、歯肉の腫れまたは圧痛、肥満症、心疾患、脳卒中、腎疾患、眼部疾患、神経損傷および高血圧からなる群から選択される、請求項10に記載の医薬組成物。
- 第2の治療剤または治療と組み合わせて医薬組成物を投与する、請求項8~11のいずれか1項に記載の医薬組成物。
- 第2の治療剤または治療が、インスリンまたはインスリンアナログ、メトホルミン、チアゾリジンジオン、スルホニルウレア、ビグアニド、クロプロパミド、グリニド、αグルコシダーゼ阻害薬、ナテグリニド、DPP4阻害薬、プラムリンチド、シタグリプチン、ブロモクリプチン、SGLT2阻害薬、カナグリフロジン、降圧薬、スタチン、アスピリン、食生活改善、エクササイズ、および栄養補助食品からなる群から選択される、請求項12に記載の医薬組成物。
- 医薬組成物を皮下、静脈内、皮内、腹腔内、経口、または筋肉内投与する、請求項8~13のいずれか1項に記載の医薬組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023030635A JP2023071827A (ja) | 2017-09-22 | 2023-03-01 | グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762562283P | 2017-09-22 | 2017-09-22 | |
US62/562,283 | 2017-09-22 | ||
PCT/US2018/052110 WO2019060653A1 (en) | 2017-09-22 | 2018-09-21 | GLP-1 RECEPTOR AGONISTS (GLUCAGON-LIKE PEPTIDE 1) AND USES THEREOF |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023030635A Division JP2023071827A (ja) | 2017-09-22 | 2023-03-01 | グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020534016A JP2020534016A (ja) | 2020-11-26 |
JP7239566B2 true JP7239566B2 (ja) | 2023-03-14 |
Family
ID=63799082
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020516667A Active JP7239566B2 (ja) | 2017-09-22 | 2018-09-21 | グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 |
JP2023030635A Pending JP2023071827A (ja) | 2017-09-22 | 2023-03-01 | グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023030635A Pending JP2023071827A (ja) | 2017-09-22 | 2023-03-01 | グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 |
Country Status (12)
Country | Link |
---|---|
US (3) | US11045522B2 (ja) |
EP (1) | EP3684793A1 (ja) |
JP (2) | JP7239566B2 (ja) |
KR (1) | KR20200054303A (ja) |
CN (1) | CN111108117A (ja) |
AU (2) | AU2018338178B2 (ja) |
CA (1) | CA3073964A1 (ja) |
EA (1) | EA202090649A1 (ja) |
IL (2) | IL273253B1 (ja) |
MX (1) | MX2020002977A (ja) |
SG (1) | SG11202001637PA (ja) |
WO (1) | WO2019060653A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022117044A1 (en) * | 2020-12-03 | 2022-06-09 | Sunshine Lake Pharma Co., Ltd. | Glp-1/gcg dual receptor agonist polypeptide and fusion protein thereof |
CN112716966B (zh) * | 2021-02-03 | 2022-05-03 | 浙江诺得药业有限公司 | 一种恩格列净药用组合物及其制备方法 |
CN113461785B (zh) * | 2021-04-13 | 2022-10-14 | 湖南中晟全肽生化有限公司 | Glp-1受体激动剂及其应用 |
CN114788876A (zh) * | 2022-02-24 | 2022-07-26 | 北京医院 | 治疗糖尿病的mRNA药物制剂及其制备方法与应用 |
CN117143242B (zh) * | 2023-10-30 | 2024-03-29 | 南京佰抗生物科技有限公司 | 抗Galectin-3蛋白的单克隆抗体组合物及应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101229610B1 (ko) | 2009-10-09 | 2013-02-05 | 한남대학교 산학협력단 | Glp-1 유사체의 융합체, 및 이를 유효성분으로 함유하는 당뇨병의 예방 또는 치료용 조성물 |
JP2016532448A (ja) | 2013-08-13 | 2016-10-20 | ジーエムエーエックス バイオファーム エルエルシー. | Glp−1rに特異的に結合する抗体およびそのglp−1との融合タンパク質 |
JP2019525732A (ja) | 2016-06-09 | 2019-09-12 | メドイミューン・リミテッドMedImmune Limited | プロテアーゼ耐性一脂質付加ペプチド |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA008831B1 (ru) | 2003-06-12 | 2007-08-31 | Эли Лилли Энд Компани | Слитые белки аналогов glp-1 |
US8257740B1 (en) | 2011-08-15 | 2012-09-04 | Gp Medical, Inc. | Pharmaceutical composition of nanoparticles |
US20060275288A1 (en) | 2005-01-20 | 2006-12-07 | Grihalde Nelson D | GLP-1 receptor agonist and allosteric modulator monoclonal antibodies and uses thereof |
US8246995B2 (en) | 2005-05-10 | 2012-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells |
US8497240B2 (en) | 2006-08-17 | 2013-07-30 | Amylin Pharmaceuticals, Llc | DPP-IV resistant GIP hybrid polypeptides with selectable properties |
AR064623A1 (es) | 2006-12-21 | 2009-04-15 | Centocor Inc | Uso de agonistas del receptor de glp -1 de accion prolongada para mejorar la sensibilidad a la insulina y los perfiles lipidicos |
WO2009020802A2 (en) | 2007-08-03 | 2009-02-12 | Eli Lilly And Company | Treatment for obesity |
ES2672770T3 (es) | 2007-09-05 | 2018-06-18 | Novo Nordisk A/S | Derivados del péptido-1 similar al glucagón y su uso farmacéutico |
PT2373681T (pt) | 2008-12-10 | 2017-04-11 | Glaxosmithkline Llc | Composições farmacêuticas de albiglutida |
US20120148586A1 (en) | 2009-08-27 | 2012-06-14 | Joyce Ching Tsu Chou | Glucagon-like protein-1 receptor (glp-1r) agonists for treating autoimmune disorders |
JP5774595B2 (ja) | 2009-10-28 | 2015-09-09 | ヤンセン バイオテツク,インコーポレーテツド | 抗glp−1r抗体及びそれらの使用 |
WO2011056713A2 (en) | 2009-11-03 | 2011-05-12 | Amylin Pharmaceuticals, Inc. | Glp-1 receptor agonist compounds for obstructive sleep apnea |
BR112015004734A2 (pt) | 2012-09-07 | 2017-11-21 | Sanofi Sa | proteínas de fusão para tratar uma síndrome metabólica |
AU2014207748B2 (en) | 2013-01-17 | 2018-10-11 | Vtv Therapeutics Llc | Combinations of a GLP1R agonist and metformin and use thereof for the treatment of type 2 diabetes and other disorders |
US20150259416A1 (en) | 2014-03-12 | 2015-09-17 | Biocrine Ab | Methods for treating and/or limiting development of diabetes |
CN104098702B (zh) * | 2014-07-23 | 2017-06-16 | 湖北工业大学 | 一种利用mfh融合蛋白制备glp‑1多肽或其类似物方法和应用 |
CN111388680B (zh) * | 2015-01-28 | 2024-01-05 | 中国科学院天津工业生物技术研究所 | 一种多肽复合物作为多肽或蛋白质药物载体的应用、方法及其融合蛋白复合物 |
CA2975633A1 (en) | 2015-02-11 | 2016-08-18 | Gmax Biopharm Llc. | Stable pharmaceutical solution formulation of glp-1r antibody fusion protein |
TWI622596B (zh) | 2015-10-26 | 2018-05-01 | 美國禮來大藥廠 | 升糖素受體促效劑 |
-
2018
- 2018-09-21 MX MX2020002977A patent/MX2020002977A/es unknown
- 2018-09-21 CN CN201880061327.6A patent/CN111108117A/zh active Pending
- 2018-09-21 EA EA202090649A patent/EA202090649A1/ru unknown
- 2018-09-21 KR KR1020207011414A patent/KR20200054303A/ko not_active Application Discontinuation
- 2018-09-21 AU AU2018338178A patent/AU2018338178B2/en active Active
- 2018-09-21 CA CA3073964A patent/CA3073964A1/en active Pending
- 2018-09-21 JP JP2020516667A patent/JP7239566B2/ja active Active
- 2018-09-21 US US16/137,662 patent/US11045522B2/en active Active
- 2018-09-21 SG SG11202001637PA patent/SG11202001637PA/en unknown
- 2018-09-21 WO PCT/US2018/052110 patent/WO2019060653A1/en unknown
- 2018-09-21 EP EP18783613.5A patent/EP3684793A1/en active Pending
- 2018-09-21 IL IL273253A patent/IL273253B1/en unknown
-
2021
- 2021-05-27 US US17/332,215 patent/US11779633B2/en active Active
-
2023
- 2023-03-01 JP JP2023030635A patent/JP2023071827A/ja active Pending
- 2023-07-19 IL IL304574A patent/IL304574A/en unknown
- 2023-08-29 US US18/457,482 patent/US20240024428A1/en active Pending
- 2023-09-04 AU AU2023223010A patent/AU2023223010A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101229610B1 (ko) | 2009-10-09 | 2013-02-05 | 한남대학교 산학협력단 | Glp-1 유사체의 융합체, 및 이를 유효성분으로 함유하는 당뇨병의 예방 또는 치료용 조성물 |
JP2016532448A (ja) | 2013-08-13 | 2016-10-20 | ジーエムエーエックス バイオファーム エルエルシー. | Glp−1rに特異的に結合する抗体およびそのglp−1との融合タンパク質 |
JP2019525732A (ja) | 2016-06-09 | 2019-09-12 | メドイミューン・リミテッドMedImmune Limited | プロテアーゼ耐性一脂質付加ペプチド |
Non-Patent Citations (3)
Title |
---|
Hye-Shin Chung et al.,The N-terminal alanine-extended GLP-1/IgG-Fc fusion protein confers resistance to DPP-IV and reduces serum glucose level in db/db mice,Regulatory Peptides,2011年,Vol.170,Issue 1-3,pp.1-3 |
Ji-Yeon Oh et al.,Novel DPP-IV-resistant Analogs of GLP-1: The N-terminal Extension of GLP-1 by a Single Amino Acid,Bulletin of the Korean Chemical Society,2009年,Vol.30,No.10,pp.2471-2474 |
Yong-Mo Kim et al.,Novel AGLP-1 albumin fusion protein as a long-lasting agent for type 2 diabetes,BMB Reports,2013年,Vol.46,Issue 12,pp.606-610 |
Also Published As
Publication number | Publication date |
---|---|
AU2023223010A1 (en) | 2023-11-09 |
JP2023071827A (ja) | 2023-05-23 |
WO2019060653A1 (en) | 2019-03-28 |
US11779633B2 (en) | 2023-10-10 |
CA3073964A1 (en) | 2019-03-28 |
IL304574A (en) | 2023-09-01 |
US20240024428A1 (en) | 2024-01-25 |
JP2020534016A (ja) | 2020-11-26 |
AU2018338178A1 (en) | 2020-04-02 |
CN111108117A (zh) | 2020-05-05 |
IL273253A (en) | 2020-04-30 |
KR20200054303A (ko) | 2020-05-19 |
US11045522B2 (en) | 2021-06-29 |
IL273253B1 (en) | 2024-03-01 |
US20210283225A1 (en) | 2021-09-16 |
MX2020002977A (es) | 2020-11-06 |
EA202090649A1 (ru) | 2020-06-29 |
EP3684793A1 (en) | 2020-07-29 |
AU2018338178B2 (en) | 2023-06-08 |
US20190091296A1 (en) | 2019-03-28 |
SG11202001637PA (en) | 2020-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7239566B2 (ja) | グルカゴン様ペプチド1受容体アゴニストおよびそれらの使用 | |
EP3331908B1 (en) | Anti-angptl8 antibodies and uses thereof | |
JP7165225B2 (ja) | レプチン受容体を活性化させる抗原結合タンパク質 | |
AU2017363143B2 (en) | Methods of treating obesity with anti-ANGPTL8 antibodies | |
JP7420730B2 (ja) | 代謝機能不全または低レプチン血症の治療に使用するためのレプチン受容体アゴニスト性抗体 | |
CA3066317A1 (en) | Methods for treating hyperlipidemia in diabetic patients by administering a pcsk9 inhibitor | |
JP2020524658A (ja) | 胃抑制ペプチド受容体(gipr)に対する結合タンパク質をglp−1アゴニストと組み合わせて使用する、代謝障害の治療方法又は寛解方法 | |
EA045412B1 (ru) | Агонисты рецептора глюкагоноподобного пептида 1 и их применения | |
CN114980916A (zh) | 用于2型糖尿病的长效glp1类似物药物 | |
WO2024064842A1 (en) | Methods of treating obesity, diabetes, and liver dysfunction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210909 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220722 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220809 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20221109 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221205 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230131 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230302 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7239566 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |