JP2019533680A - 抗肥満および抗糖尿病効能を有するペプチド、並びにその用途 - Google Patents
抗肥満および抗糖尿病効能を有するペプチド、並びにその用途 Download PDFInfo
- Publication number
- JP2019533680A JP2019533680A JP2019520822A JP2019520822A JP2019533680A JP 2019533680 A JP2019533680 A JP 2019533680A JP 2019520822 A JP2019520822 A JP 2019520822A JP 2019520822 A JP2019520822 A JP 2019520822A JP 2019533680 A JP2019533680 A JP 2019533680A
- Authority
- JP
- Japan
- Prior art keywords
- group
- seq
- peptide
- fat
- peptides
- 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.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 170
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 34
- 230000003579 anti-obesity Effects 0.000 title claims abstract description 15
- 230000003178 anti-diabetic effect Effects 0.000 title claims description 13
- 210000004369 blood Anatomy 0.000 claims abstract description 57
- 239000008280 blood Substances 0.000 claims abstract description 57
- 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 abstract description 26
- 210000001789 adipocyte Anatomy 0.000 claims abstract description 18
- 230000002366 lipolytic effect Effects 0.000 claims abstract description 15
- 108010016731 PPAR gamma Proteins 0.000 claims abstract description 11
- 230000007423 decrease Effects 0.000 claims abstract description 7
- 101001129187 Homo sapiens Patatin-like phospholipase domain-containing protein 2 Proteins 0.000 claims abstract description 5
- 102100031248 Patatin-like phospholipase domain-containing protein 2 Human genes 0.000 claims abstract description 5
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 47
- 206010012601 diabetes mellitus Diseases 0.000 claims description 46
- 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 35
- 108090000623 proteins and genes Proteins 0.000 claims description 35
- 239000008103 glucose Substances 0.000 claims description 34
- 208000008589 Obesity Diseases 0.000 claims description 29
- 235000020824 obesity Nutrition 0.000 claims description 29
- 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 claims description 26
- 102000004169 proteins and genes Human genes 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 230000004130 lipolysis Effects 0.000 claims description 11
- 102000012132 Peroxisome proliferator-activated receptor gamma Human genes 0.000 claims description 10
- 150000002632 lipids Chemical class 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
- 125000001421 myristyl group Chemical group [H]C([*])([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 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 230000004132 lipogenesis Effects 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 claims description 2
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 230000000052 comparative effect Effects 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 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 description 2
- 102000030914 Fatty Acid-Binding Human genes 0.000 claims 1
- 108091022862 fatty acid binding Proteins 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 23
- 229940079593 drug Drugs 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 17
- 238000009825 accumulation Methods 0.000 abstract description 9
- 238000002372 labelling Methods 0.000 abstract description 9
- 230000002293 adipogenic effect Effects 0.000 abstract description 5
- 102100035905 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 Human genes 0.000 abstract description 4
- 101000929840 Homo sapiens 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 Proteins 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 102000000536 PPAR gamma Human genes 0.000 abstract 1
- 230000000225 effect on diabetes Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 210000004027 cell Anatomy 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 235000009200 high fat diet Nutrition 0.000 description 26
- 235000005911 diet Nutrition 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 230000037213 diet Effects 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 230000001965 increasing effect Effects 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 13
- 238000013116 obese mouse model Methods 0.000 description 13
- 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 12
- 239000013641 positive control Substances 0.000 description 12
- 238000010171 animal model Methods 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 10
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 235000012000 cholesterol Nutrition 0.000 description 10
- 238000012258 culturing Methods 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 239000011347 resin Substances 0.000 description 10
- 229920005989 resin Polymers 0.000 description 10
- 238000010186 staining Methods 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 9
- 210000000577 adipose tissue Anatomy 0.000 description 9
- 239000002243 precursor Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 238000011740 C57BL/6 mouse Methods 0.000 description 8
- 230000035508 accumulation Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000593 degrading effect Effects 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000003472 antidiabetic agent Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000007446 glucose tolerance test Methods 0.000 description 5
- 238000012744 immunostaining Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 101100214824 Caenorhabditis elegans abhd-5.2 gene Proteins 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 4
- 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 4
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 210000003486 adipose tissue brown Anatomy 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000011191 terminal modification Methods 0.000 description 4
- 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 3
- -1 ACC Proteins 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 230000011759 adipose tissue development Effects 0.000 description 3
- 210000000593 adipose tissue white Anatomy 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000000653 nervous system Anatomy 0.000 description 3
- 239000000863 peptide conjugate Substances 0.000 description 3
- 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 3
- 210000000229 preadipocyte Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960004034 sitagliptin Drugs 0.000 description 3
- 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 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 229940122199 Insulin secretagogue Drugs 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GKXJWSZPLIKUPS-IUNAMMOKSA-N N-[(2Z,6Z)-2,6-bis(hydroxyimino)cyclohexylidene]hydroxylamine Chemical compound O\N=C1\CCC\C(=N\O)C1=NO GKXJWSZPLIKUPS-IUNAMMOKSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000002123 RNA extraction Methods 0.000 description 2
- 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 2
- 241000786103 Steatomys pratensis Species 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000883 anti-obesity agent Substances 0.000 description 2
- 229940125710 antiobesity agent Drugs 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000008004 cell lysis buffer Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000009207 exercise therapy Methods 0.000 description 2
- 229960001582 fenfluramine Drugs 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 210000001596 intra-abdominal fat Anatomy 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 238000010603 microCT Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 210000004003 subcutaneous fat Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002381 testicular Effects 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 1
- KJYAFJQCGPUXJY-UMSFTDKQSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(tritylamino)butanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KJYAFJQCGPUXJY-UMSFTDKQSA-N 0.000 description 1
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 1
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 1
- LZOLWEQBVPVDPR-VLIAUNLRSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](OC(C)(C)C)C)C(O)=O)C3=CC=CC=C3C2=C1 LZOLWEQBVPVDPR-VLIAUNLRSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 208000013824 Acidemia Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 102000014777 Adipokines Human genes 0.000 description 1
- 108010078606 Adipokines Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 108010011459 Exenatide Proteins 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
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 1
- 108010010803 Gelatin 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
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 208000001280 Prediabetic State Diseases 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 229940062328 actos Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000478 adipokine Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000002788 anti-peptide Effects 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 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 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037237 body shape Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- QEVLNUAVAONTEW-UZYHXJQGSA-L calcium;(2s)-4-[(3as,7ar)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxobutanoate;dihydrate Chemical compound O.O.[Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 QEVLNUAVAONTEW-UZYHXJQGSA-L 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000013170 computed tomography imaging Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 239000002389 essential drug Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 230000006372 lipid accumulation Effects 0.000 description 1
- 230000003520 lipogenic effect Effects 0.000 description 1
- 230000000512 lipotoxic effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- 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 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 201000008312 primary pulmonary hypertension Diseases 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([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 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 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
- C07K14/5759—Products of obesity genes, e.g. leptin, obese (OB), tub, fat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
(a)配列番号1のアミノ酸配列からなるペプチド;
(b)配列番号2または配列番号3のアミノ酸配列からなるペプチド;および
(c)配列番号6または配列番号7のアミノ酸配列からなるペプチド。
(a)配列番号1のアミノ酸配列からなるペプチド;
(b)配列番号3または配列番号4のアミノ酸配列からなるペプチド;および
(c)配列番号6または配列番号7のアミノ酸配列からなるペプチド。
合成例1:ペプチドの合成
クロロトリチルクロリドレジン(Chloro trityl chloride resin;CTL resin、Nova biochem Cat No.01‐64‐0021)700mgを反応容器に入れ、メチレンクロリド(MC)10mlを加えて3分間撹拌した。溶液を除去し、ジメチルホルムアミド(DMF)10mlを入れて3分間撹拌した後、さらに溶媒を除去した。反応器に10mlのジクロロメタン溶液を入れ、Fmoc‐Asn(Trt)‐OH(Bachem、Swiss)200mmoleおよびジイソプロピルエチルアミン(DIEA)400mmoleを入れた後、撹拌してよく溶かし、1時間撹拌しながら反応させた。反応後に洗浄し、メタノールとDIEA(2:1)をDCM(dichloromethane)に溶かして10分間反応させ、過量のDCM/DMF(1:1)で洗浄した。溶液を除去し、ジメチルホルムアミド(DMF)を10ml入れて3分間撹拌した後、さらに溶媒を除去した。脱保護溶液(20%のピペリジン(Piperidine)/DMF)10mlを反応容器に入れ、10分間常温で撹拌してから溶液を除去した。同量の脱保護溶液を入れ、さらに10分間反応を維持した後、溶液を除去し、それぞれ3分ずつDMFで2回、MCで1回、DMFで1回洗浄してAsn‐CTLレジン(Resin)を製造した。新しい反応器に10mlのDMF溶液を入れ、Fmoc‐Arg(Pbf)‐OH(Bachem、Swiss)200mmole、HoBt200mmole、およびBop200mmoleを入れた後、撹拌してよく溶かした。反応器に400mmoleのDIEAを分画で2回にわたって入れた後、全ての固体が溶けるまで少なくとも5分間撹拌した。溶かしたアミノ酸混合溶液を、脱保護されたレジンのある反応容器に入れ、1時間常温で撹拌しながら反応させた。反応液を除去し、DMF溶液で3回5分ずつ撹拌してから除去した。少量の反応レジンを取り、カイザーテスト(Ninhydrin Test)により反応程度を調べた。脱保護溶液で、上記と同様に2回脱保護反応させ、Arg‐Asn‐CTLレジンを製造した。DMFとMCで十分に洗浄し、さらに1回カイザーテストを行った後、上記と同様に下記のアミノ酸付着実験を行った。選定されたアミノ酸配列に基づき、Fmoc‐Thr(tBu)‐OH、Fmoc‐Lys(Boc)‐OH、およびFmoc‐Leu‐OHの順に連鎖反応させた。Fmoc‐保護基を脱保護溶液で10分ずつ2回反応させた後、よく洗浄して除去した。無水酢酸とDIEA、HoBtを入れてアセチル化を1時間行った後、製造されたペプチジルレジンをDMF、MC、およびメタノールでそれぞれ3回洗浄し、窒素空気をゆっくりと流して乾燥した後、P2O5下で真空減圧して完全に乾燥した後、脱漏溶液[トリフルオロ酢酸(Trifluroacetic acid)81.5%、蒸留水5%、チオアニソール(Thioanisole)5%、フェノール(Phenol)5%、EDT2.5%、およびTIS1%]30mlを入れた後、常温でたまに振りながら反応を2時間維持した。フィルタリングしてレジンを濾過し、レジンを少量のTFA溶液で洗浄した後、母液と合わせた。減圧により、全体積の半分程度残るように蒸留し、50mlの冷たいエーテルを加えて沈殿を誘導した後、遠心分離により沈殿を集め、さらに冷たいエーテルで2回洗浄した。母液を除去し、窒素下で十分に乾燥することで、精製前のNH2‐Leu‐Lys‐Thr‐Arg‐Asn‐COOHのペプチド(配列番号1)を0.85g合成(収率:92%)した。NH2‐Lys‐Gly‐Ala‐Cys(Ser)‐Thr‐Gly‐Trp‐Met‐Ala‐COOH(配列番号2)を0.78g合成し(収率:82%)、NH2‐Ala‐Cys(Ser)Thr‐Leu‐Pro‐His‐Pro‐Trp‐Phe‐Cys(Ser)‐COOH(配列番号3)を0.92g合成した(収率:85%)。NH2‐Cys(Ser)‐Asp‐Leu‐Arg‐Arg‐Leu‐Glu‐Met‐Tyr‐Cys(Ser)‐COOH(配列番号4)を0.76g合成した(収率:88%)。分子量測定機により測定したところ、配列番号1のペプチドの分子量630.7(理論値:630.7)、配列番号2のペプチドの分子量924.5(理論値:924.1)、配列番号3のペプチドの分子量1236(理論値:1236.5)、配列番号4のペプチドの分子量1301.5(理論値:1301.5)が得られた。
1‐1.脂肪前駆細胞を用いた脂質蓄積の抑制(オイルレッドO染色)
脂肪前駆細胞(pre‐adipocyte)である3T3‐L1細胞をConfluent状態まで培養した後、10ug/mlのインスリン、0.1uMのデキサメタゾン、および0.5uMのIBMXが含まれた分化培地に交換、およびペプチドを濃度毎に処理して2日間培養した。その後、2日毎に10ug/mlのインスリンが含まれた培地に交換し、10日間分化を誘導した後、細胞中の滴(droplet)の生成を確認するために、オイルレッドO染色を行った。
3X105細胞/ウェルの細胞密度で、6ウェルプレートに3T3‐L1(脂肪前駆細胞)をシーディングした。24時間培養した後、ペプチドを濃度毎(0.1、1、10ug/ml)に処理し、37℃の培養器にて14日間培養した。培養が完了された細胞を回収した後、RNA抽出溶液(Easy Blue、Intron)を処理してRNAを準備し、RTプリミックス(Intron)を用いてcDNAを合成した。各標識因子(PPARγ、ACC、aP2)に対するプライマーとPCRプリミックス(Intron)を用いてPCRを行った。次に、1%のアガロースゲルにPCR産物を5ulずつローディングして電気泳動した後、Gel‐Docでバンドを確認し、その結果を図3aおよび図3bに示した。
3X105細胞/ウェルの細胞密度で、6ウェルプレートに3T3‐L1(脂肪前駆細胞)をシーディングした。24時間培養した後、ペプチド複合体を濃度毎(0.1、1、10ug/ml)に処理し、37℃の培養器にて14日間培養した。細胞溶解バッファーを処理して溶解物を確保した後、タンパク質を定量し、脂肪生成因子である抗‐PPARγ抗体(Santa Cruz Biotechnology、USA)と脂肪分解因子である抗‐pHSL 抗体(Santa Cruz Biotechnology、USA)を用いてウエスタンブロットを行った。
2‐1.脂質分解に関与する遺伝子の発現増加
3X105細胞/ウェルの細胞密度で、6ウェルプレートに3T3‐L1(脂肪前駆細胞)をシーディングした。24時間培養した後、ペプチドを濃度毎(0.1、1、10ug/ml)に処理し、37℃の培養器にて14日間培養した(陽性対照群:100ng/mlのTNFα(SIGMA))。培養が完了された細胞を回収した後、RNA抽出溶液(Easy Blue、Intron)を処理してRNAを準備し、RTプリミックス(Intron)を用いてcDNAを合成した。各標識因子(AMPK‐α1、CGI58)に対するプライマーとPCRプリミックス(Intron)を用いてPCRを行った。次に、1%アガロースゲルにPCR産物を5ulずつローディングして電気泳動した後、Gel‐Docでバンドを確認し、その結果を図6に示した。
3X105細胞/ウェルの細胞密度で、6ウェルプレートに3T3‐L1(脂肪前駆細胞)をシーディングした。24時間培養した後、ペプチド複合体を濃度毎(0.1、1、10ug/ml)に処理し、37℃の培養器にて14日間培養した(陽性対照群:100ng/mlのTNFα(SIGMA))。細胞溶解バッファーを処理して溶解物を確保した後、タンパク質を定量し、脂肪分解因子である抗‐ATGL抗体(Santa Cruz Biotechnology、USA)を用いてウエスタンブロットを行った。
3X105細胞/ウェルの細胞密度で、6ウェルプレートに3T3‐L1(脂肪前駆細胞)をシーディングした。24時間培養した後、各ペプチドまたはペプチド複合体(1ug/ml)を処理し、37℃の培養器にて14日間培養した(陽性対照群:100ng/mlのTNFα(SIGMA))。培養が完了された細胞を70%エタノールを用いて細胞を固定した後、抗‐Phospho‐HSL抗体(Santa Cruz Biotechnology、USA)を用いて細胞免疫染色法により脂肪分解誘導因子であるphospho‐HSLの細胞中の発現を観察した。
肥満誘導マウス動物の腹部から脂肪組織を採取した後、24ウェル培養プレートにウェル当たり100mgずつ脂肪組織を入れ、培養培地(1ml Krebs‐Ringer buffer containing 25mM HEPES、5.5mM glucose、and 2%(w/v) bovine serum albumin)に培養した。培養時に、ペプチド複合体を0.1ug/ml、1ug/ml、10ug/mlの濃度で処理し、陽性対照群として100ng/mlのTNFαを処理して、48時間培養した後、脂肪が分解されながら生じたグリセロールの量を測定した。
脂肪組織は、色によって白色脂肪(White Fat)、褐色脂肪(Brown Fat)に分けられ、部位によって皮下脂肪、腹膜脂肪、腸間膜脂肪(内臓脂肪)、および副睾丸脂肪に分けられる。解剖後に各脂肪を摘出して白色脂肪を分離した後、それぞれ100mg/ウェルの重量で、24ウェルプレートに複合剤を濃度毎に処理し、培養培地(1ml Krebs‐Ringer buffer containing 25mM HEPES、5.5mM glucose、and 2%(w/v) bovine serum albumin)で72時間培養してから組織を切片化してヘマトキシリンおよびエオシンで染色し、200倍で顕微鏡(TS100、Nicon)観察して脂肪細胞の大きさを比較した。
肥満誘導マウス動物の腹部から脂肪組織を採取した後、24ウェル培養プレートにウェル当たり100mgずつ脂肪組織を入れ、培養培地(1ml Krebs‐Ringer buffer containing 25mM HEPES、5.5mM glucose、and 2%(w/v) bovine serum albumin)に培養した。培養時に、ペプチド複合体を処理し、陽性対照群として100ng/mlのTNFαを処理して、48時間培養した後、脂肪分解因子であるphospho‐HSL(緑色蛍光物質)の発現を確認した。
正常C57BL/6マウスに高脂肪食餌をさせて誘導した肥満誘導モデルDIO(Diets induced obesity)を用いて抗肥満効能実験を行い、陽性対照群薬物として、5ug/mlのTNFαを使用した。対照群は、高脂肪食餌でなく一般食餌で進行した。実験は、高脂肪食餌を12週間進行しながら、それぞれペプチド複合体または陽性対照群を処理して体重の減少を確認した。
本動物実験では、C57BL/6(正常マウス)((株)SAMTAKO)とC57BLKS/JLepr(糖尿病モデルマウス、db/dbマウス)((株)中央実験動物から購入)雄を使用し、抗糖尿病および/または抗肥満効能物質としては複合剤を使用し、陽性対照群薬物としてはシタグリプチン(sitagliptin)を使用した。
空腹血糖170mg/dL以上の45〜65歳を対象として、簡易臨床実験を行った。空腹血糖を基準として、食後30分に複合製剤を摂取させ30、60、90、120、150、180分間隔で採血し、アキュチェックアクティブ(Accu‐Chek active)(Roche)により血糖レベルを測定し、図24a〜図24dに示した。
Claims (15)
- 配列番号2または配列番号4のアミノ酸配列からなるペプチド。
- 抗肥満または抗糖尿病活性を有する、請求項1に記載のペプチド。
- N‐末端に、アセチル基(acetyl group)、フルオレニルメトキシカルボニル基(fluoreonylmethoxycarbonyl group)、ホルミル基(formyl group)、パルミトイル基(palmitoyl group)、ミリスチル基(myristyl group)、ステアリル基(stearyl group)、およびポリエチレングリコール(polyethylene glycol;PEG)からなる群から選択される保護基が結合している、請求項1に記載のペプチド。
- C‐末端に、ヒドロキシ基(hydroxyl group、‐OH)、アミノ基(amino group、‐NH2)、またはアジド(azide、‐NHNH2)が結合している、請求項1に記載のペプチド。
- PPARγ(Peroxisome proliferator‐activated receptor gamma)、ACC(Acetyl‐CoA carboxylase)、およびaP2(adipose‐specific fatty acid‐binding protein 2)からなる群から選択される1種以上の脂質生成標識因子の発現を減少させる、請求項2に記載のペプチド。
- pHSL(phospho‐hormone‐sensitive lipase)、AMPK‐α1(AMP‐activated protein kinase α1)、CGI‐58(Comparative Gene Identification‐58)、およびATGL(Adipose triglyceride lipase)からなる群から選択される1種以上の脂肪分解因子の発現を増加させる、請求項1に記載のペプチド。
- 脂肪分解を増加させる、請求項1に記載のペプチド。
- 脂質生成を抑制する、請求項1に記載のペプチド。
- 血糖を減少させる、請求項1に記載のペプチド。
- 脂肪細胞の大きさを減少させる、請求項1に記載のペプチド。
- 血中コレステロールを減少させる、請求項1に記載のペプチド。
- 配列番号2または配列番号4のアミノ酸配列からなるペプチドからなる群から選択される1種以上のペプチドを有効成分として含む、肥満の予防または治療用医薬組成物。
- 配列番号1、配列番号3、配列番号5、配列番号6、および配列番号7からなる群から選択されるアミノ酸配列からなるペプチドからなる群から選択される1種以上のペプチドをさらに含む、請求項12に記載の肥満の予防または治療用医薬組成物。
- 配列番号2または配列番号4のアミノ酸配列からなるペプチドからなる群から選択される1種以上のペプチドを有効成分として含む、糖尿病の予防または治療用医薬組成物。
- 配列番号1、配列番号3、配列番号5、配列番号6、および配列番号7からなる群から選択されるアミノ酸配列からなるペプチドからなる群から選択される1種以上のペプチドをさらに含む、請求項14に記載の糖尿病の予防または治療用医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2016-0135615 | 2016-10-19 | ||
KR1020160135615A KR101887577B1 (ko) | 2016-10-19 | 2016-10-19 | 항비만 및 항당뇨 효능을 갖는 펩타이드 및 이의 용도 |
PCT/KR2017/003448 WO2018074682A1 (ko) | 2016-10-19 | 2017-03-29 | 항비만 및 항당뇨 효능을 갖는 펩타이드 및 이의 용도 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019533680A true JP2019533680A (ja) | 2019-11-21 |
JP6875516B2 JP6875516B2 (ja) | 2021-05-26 |
Family
ID=62018812
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019520822A Active JP6875516B2 (ja) | 2016-10-19 | 2017-03-29 | 抗肥満および抗糖尿病効能を有するペプチド、並びにその用途 |
Country Status (8)
Country | Link |
---|---|
US (1) | US10723777B2 (ja) |
EP (1) | EP3530667B1 (ja) |
JP (1) | JP6875516B2 (ja) |
KR (1) | KR101887577B1 (ja) |
CN (1) | CN110088122B (ja) |
ES (1) | ES2901416T3 (ja) |
RU (1) | RU2721426C1 (ja) |
WO (1) | WO2018074682A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102288716B1 (ko) * | 2019-10-30 | 2021-08-12 | 경상남도 | 항비만 효능을 갖는 펩타이드 및 이의 용도 |
KR102112702B1 (ko) * | 2019-12-19 | 2020-05-19 | (주)슈퍼노바 바이오 | 표면 개질된 가스-생성 나노입자를 이용한 지방 분해용 조성물 |
KR20230138832A (ko) * | 2022-03-24 | 2023-10-05 | (주)케어젠 | 항당뇨 활성을 갖는 펩타이드 복합체 및 이의 용도 |
KR20230148629A (ko) | 2022-04-18 | 2023-10-25 | (주)케어젠 | 항비만 및 항당뇨 활성을 갖는 펩타이드 및 이의 용도 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5516891A (en) | 1992-06-16 | 1996-05-14 | Kinerton, Ltd. | Liquid phase synthesis of peptides and peptide derivatives |
KR100899970B1 (ko) * | 2001-02-19 | 2009-05-28 | 메르크 파텐트 게엠베하 | T-세포 에피토프의 동정 방법 및 감소된 면역원성을 갖는분자의 제조를 위한 용도 |
US20050288223A1 (en) | 2002-05-17 | 2005-12-29 | Genset S.A. | OBG3 Fragments Inhibiting The Conversion Of Active OBG3 Into Less Active OBG3 And Other Compositions For Treatment Of Metabolic Disorders |
US20070060512A1 (en) * | 2003-03-04 | 2007-03-15 | Homayoun Sadeghi | Dipeptidyl-peptidase protected protein |
CN1980686A (zh) * | 2004-04-05 | 2007-06-13 | 安斯泰来制药有限公司 | 抗肥胖药 |
US20070185025A1 (en) | 2005-09-11 | 2007-08-09 | The Trustees Of Columbia University In The City Of New York | Filoviral immunosuppressive peptides and uses thereof |
CN101914150B (zh) * | 2009-03-12 | 2013-07-17 | 刘建宁 | 一种多肽及其在制药中的应用 |
UY33462A (es) * | 2010-06-23 | 2012-01-31 | Zealand Pharma As | Analogos de glucagon |
US20150125438A1 (en) * | 2012-07-20 | 2015-05-07 | Sang Jae Kim | Anti-Inflammatory Peptides and Composition Comprising the Same |
KR20140027594A (ko) * | 2012-07-23 | 2014-03-07 | 씨지케이바이오 주식회사 | 항당뇨 및 항비만 활성을 갖는 약학 조성물 |
CA2886228A1 (en) | 2012-09-26 | 2014-04-03 | Indiana University Research And Technology Corporation | Insulin analog dimers |
KR101510742B1 (ko) * | 2013-05-13 | 2015-04-10 | (주)케어젠 | 비만세포―특이적 아팝토시스-유도용 펩타이드 및 이의 용도 |
US20170209544A1 (en) * | 2014-07-15 | 2017-07-27 | The Regents Of The University Of California | A peptide therapy to counteract insulin resistance and type 2 diabetes |
KR101669140B1 (ko) | 2015-04-28 | 2016-10-26 | (주)케어젠 | 항비만 및 항당뇨 효능을 갖는 펩타이드 및 이의 용도 |
-
2016
- 2016-10-19 KR KR1020160135615A patent/KR101887577B1/ko active IP Right Grant
-
2017
- 2017-03-29 US US16/343,559 patent/US10723777B2/en active Active
- 2017-03-29 RU RU2019115134A patent/RU2721426C1/ru active
- 2017-03-29 WO PCT/KR2017/003448 patent/WO2018074682A1/ko unknown
- 2017-03-29 CN CN201780076763.6A patent/CN110088122B/zh active Active
- 2017-03-29 ES ES17861361T patent/ES2901416T3/es active Active
- 2017-03-29 JP JP2019520822A patent/JP6875516B2/ja active Active
- 2017-03-29 EP EP17861361.8A patent/EP3530667B1/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN110088122B (zh) | 2022-12-27 |
US20200048323A1 (en) | 2020-02-13 |
KR101887577B1 (ko) | 2018-09-10 |
US10723777B2 (en) | 2020-07-28 |
RU2721426C1 (ru) | 2020-05-19 |
KR20180043428A (ko) | 2018-04-30 |
ES2901416T3 (es) | 2022-03-22 |
JP6875516B2 (ja) | 2021-05-26 |
EP3530667A4 (en) | 2019-11-27 |
WO2018074682A1 (ko) | 2018-04-26 |
CN110088122A (zh) | 2019-08-02 |
EP3530667B1 (en) | 2021-11-17 |
EP3530667A1 (en) | 2019-08-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6908085B2 (ja) | 抗肥満及び抗糖尿作用を有するペプチド及びその用途 | |
JP6875516B2 (ja) | 抗肥満および抗糖尿病効能を有するペプチド、並びにその用途 | |
OA18548A (en) | Peptide having anti-diabetic and anti-obesity effects and use thereof. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190520 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200602 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200831 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20201028 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201201 |
|
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: 20210406 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210422 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6875516 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE Ref document number: 6875516 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |