EP3600296A1 - Nouveaux composes, compositions et methodes pour le traitement de la resistance a l'insuline - Google Patents
Nouveaux composes, compositions et methodes pour le traitement de la resistance a l'insulineInfo
- Publication number
- EP3600296A1 EP3600296A1 EP18710891.5A EP18710891A EP3600296A1 EP 3600296 A1 EP3600296 A1 EP 3600296A1 EP 18710891 A EP18710891 A EP 18710891A EP 3600296 A1 EP3600296 A1 EP 3600296A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- group
- compound
- insulin
- hydrogen atom
- 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.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 245
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 82
- 206010022489 Insulin Resistance Diseases 0.000 title claims abstract description 65
- 238000000034 method Methods 0.000 title claims description 32
- 239000000203 mixture Substances 0.000 title description 13
- 238000011282 treatment Methods 0.000 claims abstract description 54
- 101150101862 GRB14 gene Proteins 0.000 claims abstract description 41
- 102000003746 Insulin Receptor Human genes 0.000 claims abstract description 39
- 108010001127 Insulin Receptor Proteins 0.000 claims abstract description 39
- 230000003993 interaction Effects 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 20
- 230000002401 inhibitory effect Effects 0.000 claims description 77
- 125000004432 carbon atom Chemical group C* 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 37
- 230000007170 pathology Effects 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 30
- 239000003112 inhibitor Substances 0.000 claims description 28
- -1 dioxothioxotetrahydro-pyrimidinylidene Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 229940124530 sulfonamide Drugs 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- 230000002265 prevention Effects 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims description 14
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 13
- 238000009833 condensation Methods 0.000 claims description 12
- 230000005494 condensation Effects 0.000 claims description 12
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 9
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 201000001421 hyperglycemia Diseases 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 claims description 7
- 229960003105 metformin Drugs 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 7
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 6
- 229940123208 Biguanide Drugs 0.000 claims description 6
- 206010063547 Diabetic macroangiopathy Diseases 0.000 claims description 6
- 206010054044 Diabetic microangiopathy Diseases 0.000 claims description 6
- 239000007821 HATU Substances 0.000 claims description 6
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 6
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 6
- 150000004283 biguanides Chemical class 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 201000009101 diabetic angiopathy Diseases 0.000 claims description 6
- 229940125753 fibrate Drugs 0.000 claims description 6
- 208000004104 gestational diabetes Diseases 0.000 claims description 6
- 239000012026 peptide coupling reagents Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000001467 thiazolidinediones Chemical class 0.000 claims description 6
- GQIRIWDEZSKOCN-UHFFFAOYSA-N 1-chloro-n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C(Cl)=C(C)C GQIRIWDEZSKOCN-UHFFFAOYSA-N 0.000 claims description 5
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 5
- 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 claims description 5
- 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 claims description 5
- 206010049287 Lipodystrophy acquired Diseases 0.000 claims description 5
- 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 claims description 5
- 229940100389 Sulfonylurea Drugs 0.000 claims description 5
- 208000037849 arterial hypertension Diseases 0.000 claims description 5
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 5
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 5
- 208000006132 lipodystrophy Diseases 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 5
- 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 claims description 5
- 108010011459 Exenatide Proteins 0.000 claims description 4
- ZWPRRQZNBDYKLH-VIFPVBQESA-N Gemigliptin Chemical compound C([C@@H](N)CC(=O)N1CC2=C(C(=NC(=N2)C(F)(F)F)C(F)(F)F)CC1)N1CC(F)(F)CCC1=O ZWPRRQZNBDYKLH-VIFPVBQESA-N 0.000 claims description 4
- 229940122355 Insulin sensitizer Drugs 0.000 claims description 4
- 108010019598 Liraglutide Proteins 0.000 claims description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims description 4
- 229960001667 alogliptin Drugs 0.000 claims description 4
- 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 claims description 4
- 229960001519 exenatide Drugs 0.000 claims description 4
- 229960002458 gemigliptin Drugs 0.000 claims description 4
- 229960002397 linagliptin Drugs 0.000 claims description 4
- 229960002701 liraglutide Drugs 0.000 claims description 4
- 229960004937 saxagliptin Drugs 0.000 claims description 4
- 108010033693 saxagliptin Proteins 0.000 claims description 4
- 229960004034 sitagliptin Drugs 0.000 claims description 4
- 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 4
- 229960001254 vildagliptin Drugs 0.000 claims description 4
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 4
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 claims description 3
- JPBSJQZUINELEA-UHFFFAOYSA-N 1,2-oxazole-3-sulfonamide Chemical class NS(=O)(=O)C=1C=CON=1 JPBSJQZUINELEA-UHFFFAOYSA-N 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 1
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 claims 1
- 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 145
- 102000004877 Insulin Human genes 0.000 description 69
- 108090001061 Insulin Proteins 0.000 description 69
- 229940125396 insulin Drugs 0.000 description 69
- 210000004027 cell Anatomy 0.000 description 36
- 230000000694 effects Effects 0.000 description 30
- 238000000225 bioluminescence resonance energy transfer Methods 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 22
- 239000012528 membrane Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 230000007423 decrease Effects 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- 230000037361 pathway Effects 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 10
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 10
- 102000038030 PI3Ks Human genes 0.000 description 9
- 108091007960 PI3Ks Proteins 0.000 description 9
- 238000011002 quantification Methods 0.000 description 9
- 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 8
- 230000004110 gluconeogenesis Effects 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 230000004132 lipogenesis Effects 0.000 description 8
- 101100297694 Arabidopsis thaliana PIP2-7 gene Proteins 0.000 description 7
- 101100456541 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) MEC3 gene Proteins 0.000 description 7
- 101100483663 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UFD1 gene Proteins 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 7
- 102000051325 Glucagon Human genes 0.000 description 6
- 108060003199 Glucagon Proteins 0.000 description 6
- 101150090959 Grb10 gene Proteins 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 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 6
- 229960004666 glucagon Drugs 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 150000003456 sulfonamides Chemical class 0.000 description 6
- CQCKLDAUFPKXPU-SNAWJCMRSA-N (e)-3-(5-methylfuran-2-yl)prop-2-enoic acid Chemical compound CC1=CC=C(\C=C\C(O)=O)O1 CQCKLDAUFPKXPU-SNAWJCMRSA-N 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- 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 5
- 108010074436 Sterol Regulatory Element Binding Protein 1 Proteins 0.000 description 5
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 5
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 5
- 238000000749 co-immunoprecipitation Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 230000007115 recruitment Effects 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- OUDFNZMQXZILJD-UHFFFAOYSA-N 5-methyl-2-furaldehyde Chemical compound CC1=CC=C(C=O)O1 OUDFNZMQXZILJD-UHFFFAOYSA-N 0.000 description 4
- 101150052409 GRB7 gene Proteins 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 210000000577 adipose tissue Anatomy 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 108010042209 insulin receptor tyrosine kinase Proteins 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 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 4
- 239000013612 plasmid Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 229960000654 sulfafurazole Drugs 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 108700031835 GRB10 Adaptor Proteins 0.000 description 3
- 102000053334 GRB10 Adaptor Human genes 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class 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 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 3
- 102100036264 Glucose-6-phosphatase catalytic subunit 1 Human genes 0.000 description 3
- 101710099339 Glucose-6-phosphatase catalytic subunit 1 Proteins 0.000 description 3
- 101100041816 Homo sapiens SCD gene Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 3
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 3
- 108090000472 Phosphoenolpyruvate carboxykinase (ATP) Proteins 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 101150097713 SCD1 gene Proteins 0.000 description 3
- 102100028897 Stearoyl-CoA desaturase Human genes 0.000 description 3
- 102100026839 Sterol regulatory element-binding protein 1 Human genes 0.000 description 3
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000004026 insulin derivative Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 230000008520 organization Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000004850 protein–protein interaction Effects 0.000 description 3
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 239000013598 vector Substances 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
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 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 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- DVJAMEIQRSHVKC-BDAKNGLRSA-N Dutogliptin Chemical compound OB(O)[C@@H]1CCCN1C(=O)CN[C@H]1CNCC1 DVJAMEIQRSHVKC-BDAKNGLRSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 2
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 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 2
- YHIPILPTUVMWQT-UHFFFAOYSA-N Oplophorus luciferin Chemical compound C1=CC(O)=CC=C1CC(C(N1C=C(N2)C=3C=CC(O)=CC=3)=O)=NC1=C2CC1=CC=CC=C1 YHIPILPTUVMWQT-UHFFFAOYSA-N 0.000 description 2
- 102100034792 Phosphoenolpyruvate carboxykinase [GTP], mitochondrial Human genes 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical compound CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000008078 Sterol Regulatory Element Binding Protein 1 Human genes 0.000 description 2
- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 2
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-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
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 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 2
- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 description 2
- 239000013066 combination product Substances 0.000 description 2
- 229940127555 combination product Drugs 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000001610 euglycemic effect Effects 0.000 description 2
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 2
- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 description 2
- 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 2
- NSJYMFYVNWVGON-UHFFFAOYSA-N glisentide Chemical compound COC1=CC=CC=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCC2)C=C1 NSJYMFYVNWVGON-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000000910 hyperinsulinemic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 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
- 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 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical class 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 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000000276 sedentary effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- WNVMEYJIQAAXGD-SNAWJCMRSA-N (e)-3-(5-methylfuran-2-yl)prop-2-enoyl chloride Chemical compound CC1=CC=C(\C=C\C(Cl)=O)O1 WNVMEYJIQAAXGD-SNAWJCMRSA-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
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- LGCYVLDNGBSOOW-UHFFFAOYSA-N 2H-benzotriazol-4-ol 1-hydroxybenzotriazole Chemical compound OC1=CC=CC2=C1N=NN2.C1=CC=C2N(O)N=NC2=C1 LGCYVLDNGBSOOW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 208000011732 Abnormal glucose homeostasis Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 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
- VWVKUNOPTJGDOB-BDHVOXNPSA-N Anhydrous tofogliflozin Chemical compound C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 VWVKUNOPTJGDOB-BDHVOXNPSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 description 1
- OBWASQILIWPZMG-UHFFFAOYSA-N Empagliflozin Chemical compound OC1C(O)C(O)C(CO)OC1C1=CC=C(Cl)C(CC=2C=CC(OC3COCC3)=CC=2)=C1 OBWASQILIWPZMG-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 108010057186 Insulin Glargine Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- FYZPCMFQCNBYCY-WIWKJPBBSA-N Insulin degludec Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)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](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC(O)=O)C(O)=O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC FYZPCMFQCNBYCY-WIWKJPBBSA-N 0.000 description 1
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 1
- 108091092195 Intron Proteins 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
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 101001116436 Mus musculus Xaa-Pro dipeptidase Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102100030264 Pleckstrin Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 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
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- 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 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 210000000593 adipose tissue white Anatomy 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical group 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960002174 ciprofibrate Drugs 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 229950003693 dutogliptin Drugs 0.000 description 1
- 230000001614 effect on membrane Effects 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
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960001764 glibornuride Drugs 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- 229960001381 glipizide Drugs 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
- 229960003468 gliquidone Drugs 0.000 description 1
- 229950008402 glisentide Drugs 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
- 229950002888 glyclopyramide Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005734 heterodimerization reaction Methods 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
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960004717 insulin aspart Drugs 0.000 description 1
- 108010050259 insulin degludec Proteins 0.000 description 1
- 229960003948 insulin detemir Drugs 0.000 description 1
- 229960002869 insulin glargine Drugs 0.000 description 1
- 229960002068 insulin lispro Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- UGOZVNFCFYTPAZ-IOXYNQHNSA-N levemir Chemical compound CCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=2C=CC=CC=2)C(C)C)CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)CSSC[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC2=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 UGOZVNFCFYTPAZ-IOXYNQHNSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 108010026735 platelet protein P47 Proteins 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 231100000191 repeated dose toxicity Toxicity 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical class O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000012353 t test Methods 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
- 230000008685 targeting Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229950006667 tofogliflozin Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 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
- 229960005371 tolbutamide Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229960001729 voglibose Drugs 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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to inhibitors of the interaction between the Grb14 protein and the insulin receptor for use for therapeutic purposes, in particular for the treatment of insulin resistance and for the prevention and treatment of pathologies. associated with insulin resistance.
- the invention also relates to a method for synthesizing these inhibitors and pharmaceutical compositions comprising said inhibitors.
- Type 2 diabetes represents 90% of the diabetes encountered in the world. It is largely the result of overweight and sedentary lifestyle. The annual cost of health care in the United States for diabetes was estimated at $ 245 billion in 2012. The prevention and treatment of metabolic diseases such as type 2 diabetes have become a major health care priority . In addition, abnormal glucose homeostasis is associated directly and indirectly with hypertension and alterations in lipid metabolism, and patients with type 2 diabetes have a significantly increased risk of macrovascular and microvascular complications, such as arterial hypertension, diabetic microangiopathy, or diabetic macroangiopathy.
- Metformin is generally recommended as a first-line treatment.
- Other drugs include: other biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, alpha-glucosidase inhibitors, glinides, fibrates, SGLT2 inhibitors and glucagon-like peptide-1 (GLP1) analogues. Most people do not initially need insulin, but insulin therapy may be associated with an oral drug.
- insulin resistance results in impaired insulin signaling and reduced effectiveness of conventional therapeutic approaches.
- insulin resistance develops before the onset of hyperglycemia and is associated with an increase in insulin production. After several years, the increase in insulin secretion is no longer sufficient to compensate for insulin-dependent insulin-dependent tissue resistance and the subject becomes hyperglycemic.
- Pancreatic beta cells can no longer produce enough insulin to compensate for decreased insulin sensitivity, they begin to lose their function and apoptosis is triggered. Thus, in parallel with the development of insulin resistance, there is a progressive loss of the functional mass of pancreatic cells. Ultimately, this loss of functional mass of cells is such that the pancreas is no longer able to compensate for loss of insulin sensitivity, leading to the onset of type 2 diabetes.
- none of the drugs usually used for the treatment of diabetes is recognized to permanently block the natural evolution of the pathology. Thus, more than half of the "pre-diabetic" population will develop type 2 diabetes after 4 to 5 years of treatment. For example, metformin would reduce the risk of diabetes by only 4%.
- Grb14 is a highly expressed molecular adapter in insulin-sensitive tissues (liver, adipose tissue, muscle), which binds to the activated insulin receptor and inhibits its catalytic activity.
- the expression of Grb14 is increased in adipose tissue of type 2 diabetic patients as well as in different animal models of insulin resistance, suggesting that this protein may be involved in the reduction of insulin signaling.
- the peptide domains of the Grb7 family of proteins involved in the inhibition of insulin receptor tyrosine kinase activity have been identified in WO200055634, yet this patent application does not propose molecules that can effectively treat insulin resistance.
- WO200055634 yet this patent application does not propose molecules that can effectively treat insulin resistance.
- the invention therefore aims to overcome the disadvantages of the prior art.
- the invention aims to provide novel inhibitors of the interaction between Grb14 and the insulin receptor for use for therapeutic purposes. These molecules may especially be used in pharmaceutical compositions for therapeutic purposes.
- the present invention provides novel compositions based on these inhibitors for use in the treatment of insulin resistance.
- the compositions and methods provided by the inventors may be used to treat a subject suffering from insulin resistance.
- the compositions and methods provided by the inventors can be used to treat a subject suffering, at risk of suffering or likely to suffer from a pathology associated with insulin resistance.
- Another object of the present invention is to provide a process for the preparation of these compounds.
- the invention relates to a compound that inhibits the interaction between a Grb14 protein and an insulin receptor selected from the group consisting of compounds belonging to the family of sulfonamide isoxazoles of formula (I) , their salts, solvates and / or diastereoisomers,
- the group R 1 represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms
- the groups R2, R3, R4 and R5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms; or in the group consisting of compounds belonging to the family of dioxothioxotetrahydro-pyrimidinylidene of formula (II), their salts, solvates, and / or diastereoisomers,
- the group Re represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms or a - (C 1 -C 5 alkyl) aryl group, said aryl being substituted by one or more groups chosen from groups following: -CO2R11, COR12, -OC (O) R13, -S (O) R14, -
- the group Re represents a hydrogen atom or an aryl group
- the group Rg represents a hydrogen atom or an alkoxyl group
- the groups R to R20 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms,
- the compound inhibiting the interaction between a Grb14 protein and an insulin receptor is a small molecule.
- small molecule it is to be understood, within the meaning of the invention, a natural or synthetic compound having a molecular weight of less than 1200 Da, for example between 200 and 1100 Da, and preferably between 300 and 900 Da.
- the compounds of general formula (I) and (II) are non-toxic, penetrate the membranes and in particular stimulate the PI3K pathway. There is also a specificity of inhibition of the Grb14 / IR interaction with respect to the Grb10 / IR interaction.
- compositions of the invention are used to increase lipogenesis and reduce gluconeogenesis and in particular increase the action of insulin on the expression of genes involved in lipogenesis and gluconeogenesis.
- the inhibitors according to the invention are non-toxic compounds that penetrate the membranes and particularly stimulate the PI3K pathway.
- these molecules specifically block the interaction between Grb14 and the insulin receptors and do not interfere with the interaction between Grb10 and the insulin receptors. These compounds are useful for therapeutic interventions for the treatment of insulin resistance and the prevention or treatment of conditions associated with insulin resistance.
- the group R 1 represents a linear or branched chain alkyl group containing up to 5 carbon atoms
- the groups R2 and R3 represent a hydrogen atom
- the groups FU and R5 represent a methyl group.
- the inhibiting compound of formula (I) is chosen from the group consisting of compounds of formula (Ia) or (Ib),
- the inhibiting compound of formula (II) is selected from the group consisting of compounds of formula (IIc), (IId), (IIc), or (IIf)
- the inhibitor compound according to the invention is intended for use as an insulin sensitizer.
- the invention further relates to a pharmaceutical composition comprising at least one inhibiting compound of formula (I) or formula (II) according to the invention.
- the pharmaceutical composition according to the invention further comprises at least one other active ingredient chosen from: sulfonylureas, biguanides such as metformin, thiazolidinediones, GLP1 analogs such as exenatide or liraglutide, dipeptidyl inhibitors peptidase-4 such as gliptin, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin or alogliptin, alpha-glucosidase inhibitors, glinides, fibrates or SGLT2 inhibitors such as canaglifozin .
- active ingredient chosen from: sulfonylureas, biguanides such as metformin, thiazolidinediones, GLP1 analogs such as exenatide or liraglutide, dipeptidyl inhibitors peptidase-4 such as gliptin, sitagliptin, vil
- the pharmaceutical composition according to the invention is intended for use for therapeutic purposes in a subject subjected to insulin therapy, said insulin therapy comprising insulin or an insulin analogue.
- the pharmaceutical composition according to the invention is a combination product for simultaneous, joint or separate, or sequential use for therapeutic purposes.
- the invention also relates to the inhibiting compound according to the invention or to the pharmaceutical composition according to the invention for their use in the treatment of insulin resistance as well as for the prevention or treatment of a pathology associated with insulin resistance.
- the pathology associated with insulin resistance is selected from: metabolic syndrome, polycystic ovary syndrome, obesity, pre-gestational diabetes, type 2 diabetes, hyperglycemia, lipodystrophy, diabetic nephropathy, or cardiovascular complications such as arterial hypertension, diabetic microangiopathy, or diabetic macroangiopathy,
- the inhibitory compound according to the invention is administered at a dose of between 50 mg and 250 mg per day, preferably between 100 mg and 200 mg per day.
- the invention also relates to a process for the synthesis of an inhibiting compound according to formula (I), or its diastereoisomers, comprising a step of condensation of a sulphonamide of formula (V)
- R 4 and R 5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms; with an acrylic acid derivative of formula (IV)
- the group R 1 represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms
- the groups R2 and R3 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms.
- said condensation step is carried out in the presence of DIPEA (N-ethyl-N- (propan-2-yl) propan-2-amine) and a peptide coupling reagent selected from HATU (1 - [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate) and Ghosen's reagent (1 -chloro-N, N, 2-trimethylpropenylamine).
- DIPEA N-ethyl-N- (propan-2-yl) propan-2-amine
- a peptide coupling reagent selected from HATU (1 - [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
- Ghosen's reagent (1 -chloro-N, N, 2-trimethylprop
- Figure 1 the inhibitory effect of the compound of formula (Ia) (Comp la) according to the invention (black bars) on the IR / Grb14 interaction measured by the BRET IR-Luc / Grb14-YFP technique in acellular system , compared to control (white bars), in the presence or absence of 100 nM insulin pre-stimulation (Ins).
- the results expressed as a percentage of the DMSO (dimethylsulfoxide) control, are the average calculated on the basis of 2 to 8 independent experiments ( ** p ⁇ 0.01, *** p ⁇ 0.001, by Bonferroni Multiple comparison test).
- FIG. 2 the inhibitory effect of the compound of formula (Ia) according to the invention (black bars) on the IR / Grb14 interaction as measured by co-immunoprecipitation in acellular system, compared to control (white bars), with western blot analysis of the amount of IR-Luc co-precipitated with Grb14-YFP and densitometric quantification of the revealed signals.
- the results expressed as a percentage of the DMSO (Dimethylsulfoxide) control, are the average of 2 to 8 independent experiments ( *** p ⁇ 0.001, by Bonferroni Multiple comparison test).
- FIG. 3A and FIG. 3B the inhibitory effect of the compound of formula (Ia) according to the invention (black bars) on the interaction between Grb14 and the IR tyrosine kinase domain (IRTK-Grb14 interaction) as measured by co-immunoprecipitation with Western blot analysis of the amount of IRTK48-Rluc co-precipitated with Grb14 ( Figure 3A) or Grb10 ( Figure 3B) fused to YFP and densitometric quantification of the revealed signals.
- the results expressed as a percentage of the DMSO (dimethylsulfoxide) control, are the average of 3 independent experiments ( ** p ⁇ 0.01, by t-test).
- Figure 4 the effect of the compound of formula (la) (black bars) on the growth and survival of HEK293T cells measured after 72 h of culture compared to DMSO control (Dimethylsulfoxide, white bars).
- the histograms represent the growth rate of the cells determined by the ratio: Fluorescence at D3 / Fluorescence at OJ.
- the results are the average of 3 independent experiments made in triplicates.
- FIGS. 5A and 5B show the effect of the compound of formula (Ia) according to the invention (black bars) on the activation of the PI3K / Akt pathway measured by the BRET Luc-Akt-PH / YFP-membrane technique by relative to the control DMSO (dimethylsulfoxide, white bars) as measured on (FIG. 5A) of the HEK293T cells pre-incubated or not for 1 h with the tyrosine kinase inhibitor AG1024 at a concentration of 25 ⁇ final or on (FIG. 5B) a MCF7 line doubled stably transfected with the vectors encoding Luc-Akt-PH and YFP-membrane.
- the results, expressed as BRET delta, are the average of 3 to 8 independent experiments ( ** p ⁇ 0.01, *** p ⁇ 0.001, by Newman-Keuls multiple comparison test).
- FIG. 6 the effect of the compound of formula (Ia) according to the invention (black bars) on the expression of the target genes of insulin, PEPCK (FIG. 6A) and G6Pase (FIG. 6B), involved in the pathway of gluconeogenesis
- the hepatocytes in primary culture are cultured for 8 h in the presence of compound of formula (Ia) (50 ⁇ l), insulin (1 nM) and glucagon (preincubation for 1 h at 10 nM).
- the relative quantification of the mRNAs is carried out by RT-qPCR.
- the values are related to the quantification of 18S gene from the same sample to normalize the results.
- the results are the average of 3 to 5 independent experiments ( * p ⁇ 0.05, ** p ⁇ 0.01, by Anova followed by a Newman-Keuls test).
- FIG. 7 the effect of the compound of formula (Ia) according to the invention (black bars) on the expression of insulin target genes, SREBP-1c, ACC, FAS and SCD1 (FIGS. 7AA respectively) involved in the way of lipogenesis.
- the hepatocytes in primary culture are cultured in the presence of 5 mM glucose (G5) or 25 mM glucose (G25) and 10 nM insulin for 24 h.
- the relative quantification of the mRNAs is carried out by RT-qPCR.
- the values are related to the quantification of the 18S gene of the same sample in order to normalize the results.
- the results are the average of 3 to 5 independent experiments ( * p ⁇ 0.05 by Anova followed by a Newman-Keuls test).
- the present invention provides a novel therapeutic approach for the treatment of insulin resistance.
- the invention relates to novel small molecule compounds which inhibit the interaction between the Grb14 protein and the insulin receptor, as well as pharmaceutical compositions comprising such compounds for use in therapeutic purposes.
- the invention also relates to therapeutic methods using such compounds.
- the compounds, compositions and methods allow more particularly the treatment of insulin resistance and the prevention and treatment of pathologies associated with insulin resistance.
- the "Grb14 protein” corresponds, within the meaning of the invention, to a protein belonging to the Grb7 family of molecular adapters.
- the Grb7 family of molecular adapters consists of three members: Grb7, Grb10 and Grb14. All three bind to the activated, phosphorylated insulin receptor. However, only Grb10 and Grb14 appear to play an important role in regulating the action of insulin (Holt & Siddle 2005, Desbuquois et al., 2013).
- the Grb14 protein (NP_001290351, NP 004481, UniProtKB-Q14449), encoded by the grb14 gene (Gene ID: 2888), has different isoforms defined by their parent species: hGrbl 4 for humans, rGrbl 4 for rats, and mGrb14 for the mouse.
- Grb14 is known to be strongly expressed in the skeletal muscle, white adipose tissue, heart, brain, pancreas and kidneys as well as in the liver and retina.
- the insulin receptor is encoded by a single gene comprising 22 exons and 21 introns (Gene ID: 3643).
- the insulin receptor is localized to the plasma membrane of most cells, but is most strongly found in insulin-sensitive tissues such as liver, muscle, and adipose tissue. It is also well expressed in ⁇ cells of the pancreas, in the vascular endothelium as well as in certain specific areas of the brain.
- the inhibitor of the interaction between a protein Grb14 and an insulin receptor corresponds to a compound capable of inhibiting the interaction between a protein Grb14 and a receptor of the invention. 'insulin.
- said inhibitor is preferably specific for the Grb14 protein and / or the insulin receptor, that is to say that it does not inhibit the interaction of the adapters of the same family with the insulin receptor, especially Grb10.
- the "insulin-sensitive tissues” correspond to the liver, pancreas, muscles, adipose tissue (white and brown) and the brain.
- insulin resistance also called “insulin resistance” corresponds to the insensitization of membrane cell receptors to insulin.
- insulin does not do as much effect on these receptors.
- glucose does not penetrate the cells so much, and as a result, it accumulates in the blood and lymphatic circulation, leading to an increase in blood glucose. This increase in turn stimulates hypersecretion of insulin by the pancreas and after a number of years pancreatic cells are depleted.
- the clinical profile of persons susceptible or at risk of developing insulin resistance frequently includes at least one, preferably several, more preferably at least three, of the following characteristics: excess weight (BMI greater than 25), abdominal distribution abnormal fat (waist circumference greater than 80 cm in the female, at 94 cm in humans), a sedentary lifestyle, a family history of type 2 diabetes, high blood pressure.
- Insulin resistance can be diagnosed by many methods known to those skilled in the art, including measuring glucose tolerance, measuring fasting insulin levels, measuring insulin sensitivity by intravenous administration of glucose and insulin (hyperinsulinemic euglycemic clamp). The preferred method for measuring insulin resistance is the euglycemic hyperinsulinemic clamp.
- pathology associated with insulin resistance is meant, within the meaning of the invention, any pathology or condition that is the consequence of said insulin resistance or one of its comorbidities.
- pathologies are of preference selected from: metabolic syndrome, polycystic ovary syndrome, obesity, gestational diabetes, type 2 diabetes, hyperglycemia, lipodystrophy, diabetic nephropathy or cardiovascular complications such as as arterial hypertension, diabetic microangiopathy (including diabetic neuropathy and diabetic retinopathy), and diabetic macroangiopathy.
- metabolic syndrome is meant, within the meaning of the invention, a pathology characterized by a plurality of physiological and biochemical abnormalities, asymptomatic, which can coexist with genetic and acquired factors.
- diagnosis of the metabolic syndrome can be made using the following methods: that of the World Health Organization (WHO) (WHO consultation 1999), that of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP) III of 2001) and that of the International Diabetes Federation (IDF 2005) (Zimmet et al., 2005).
- the diagnosis is made by the IDF method 2005.
- the designation of a compound is intended to designate the compound per se, as well as any salt, hydrate, or pharmaceutically acceptable stereoisomer thereof. In a more preferred embodiment, the designation of a compound is intended to mean the compound as specifically designated per se, as well as any pharmaceutically acceptable salt thereof.
- salt and / or solvate means, in the context of the present invention, a salt or solvate of a compound according to the invention, preferably pharmaceutically acceptable and having the pharmacological activity of the corresponding compound.
- salt refers to a pharmaceutically acceptable, inorganic or organic acid or base addition salt of a compound of the present invention. Salt formation typically involves associating an acidic, basic or zwitterionic molecule with a counter ion to create a saline version of the compound.
- solvates corresponds to conventional solvates such as those produced during the last stage of the preparation of the compounds of the invention because of the presence of solvents.
- solvates due to the presence of water (these solvates are also called hydrates) or of ethanol.
- the "stereoisomers” are compounds of the same semi-developed formula, but which differ in the arrangement of the atoms in space.
- the "enantiomers” are stereoisomers which are symmetrical to one another in a mirror and not superimposable.
- the "diastereoisomers” are stereoisomers which are not enantiomers. That is to say that diastereoisomers have the same sequence of atoms, but which are neither superimposable nor image of one another in a mirror.
- the double bond stereochemistry is described either in cis or in trans, with reference to the relative position of the substituents on either side of a double bond.
- subject is meant to describe here any member of the animal kingdom, preferably mammals and more preferably the man.
- prevention it should be understood in the context of the present invention to prevent or delay the occurrence of clinical or biochemical manifestations associated with the pathology.
- prevention refers to the fact of preventing or delaying the onset or reducing the intensity of pathologies associated with insulin resistance.
- insulin resistance for example to prevent or delay the onset or decrease the intensity of type 2 diabetes.
- Prevention can preferably be implemented in subjects considered at risk or predisposed to develop the pathology.
- treatment refers to the treatment of a declared condition or pathology or to reduce the symptoms and / or progression.
- treatment includes a clinical or biochemical improvement in the condition or pathology of the subject. Therefore, such treatment can be used in a subject suffering from insulin resistance to delay its progression, reduce or eliminate its effects and thus cure this condition.
- Such treatment may also be used in a subject suffering from a pathology associated with insulin resistance such as metabolic syndrome, polycystic ovary syndrome, obesity, pre-gestational diabetes, type 2 diabetes, hyperglycemia, lipodystrophy, diabetic nephropathy, or cardiovascular complications such as high blood pressure, diabetic microangiopathy, or diabetic macroangiopathy.
- administering means in the context of the present invention that a compound of interest is delivered or dispensed to a subject by any appropriate mode of administration, which can be easily determined. by the skilled person according to the nature of said compound.
- said compound may be delivered or dispensed to said subject as appropriate orally, transdermally, or parenterally such as by subcutaneous, intravenous, intramuscular, or intraperitoneal injection.
- the term "pharmaceutically effective amount” means a quantity or a prophylactic or therapeutic concentration of a compound of interest, that is to say a quantity or concentration of said compound sufficient to to treat insulin resistance and / or to prevent or treat conditions associated with insulin resistance, or to treat insulin resistance or said pathology once reported, or to reduce its symptoms and / or progression. Those skilled in the art are able to determine this so-called pharmaceutically effective amount.
- alkyl group linear, cyclic or branched, containing up to 5 carbon atoms
- C5 alkyl Cr corresponds to a saturated hydrocarbon chain, linear cyclic or branched, containing 1 to 5 carbon atoms or a linear or branched unsaturated hydrocarbon chain containing 2 to 5 carbon atoms.
- a saturated hydrocarbon chain, linear, cyclic or branched, containing from 1 to 5 carbon atoms includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl, cyclopropyl, cyclobutyl, cyclopentyl and the like.
- a linear or branched unsaturated hydrocarbon chain containing from 2 to 5 carbon atoms comprises at least one double or triple bond and includes, but is not limited to, ethene, propene, butene, pentene, ethenyl, propenyl, butenyl, pentenyl and the like.
- aryl group denotes an aromatic hydrocarbon group preferably comprising 6 to 10 carbon atoms and comprising one or more, in particular 1 or 2, condensed rings, such as, for example a phenyl group or a naphthyl group.
- this designates a phenyl group.
- - (C 1 -C 5 alkyl) -aryl refers to an aryl group as defined above bonded to the molecule via a C 1 -C 5 alkyl group such as as defined above.
- the - (C 1 -C 5 alkyl) aryl group according to the invention is a benzyl group.
- the attachment is indicated by "-”.
- “- (C 1 -C 5) alkyl-aryl” refers to an alkyl radical bonded to an aryl radical in which the alkyl is bonded to the rest of the molecule.
- the aryl group according to the present invention may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxyl (alkoxyl), hydroxyl, carboxyl or ester.
- substituted phenyl groups are methoxyphenyl, dimethoxyphenyl and carboxyphenyl.
- substituted means that any one of the hydrogen atoms may be replaced by a substituent, such as a carboxyl group.
- the compound inhibiting the interaction between a Grb14 protein and an insulin receptor is a small molecule.
- small molecule it is to be understood within the meaning of the invention, a natural or synthetic compound having a molecular weight between 200 and 1100 Da, preferably between 300 and 900 Da.
- These small molecules are generally more malleable by synthetic chemistry techniques than other classes of protein-protein interaction modulators such as peptide compounds.
- they generally have a great structural complexity which gives them a high selectivity with respect to their target and good binding affinity.
- they may have a high bioavailability and ability to cross membranes.
- the subject of the invention is an inhibitory compound for the interaction between a Grb14 protein and an insulin receptor chosen from the group consisting of compounds belonging to the family of sulphonamide isoxazoles of formula (I), their salts, solvates and / or diastereoisomers
- the group R 1 represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms
- the groups R 2, R 3, R 4 and R 5 are identical or different and represent a hydrogen atom or an alkyl group; linear, cyclic or branched chain containing up to 5 carbon atoms; or in the group consisting of compounds belonging to the family of dioxothioxotetrahydro-pyrimidinylidenes of formula (II), their salts, solvates, and / or diastereoisomers,
- the group Re represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms or a - (C 1 -C 5 alkyl) aryl group, said aryl being substituted by one or more groups chosen from groups following: -CO2R11, COR12, -OC (0) Ri3, -S (0) Ri4, - OR15, -SR16, -SO2Ri7, -CONRi8Ri9, -OCO 2 R 20,
- the group R 7 represents a hydrogen atom or a carboxyl group
- the group Re represents a hydrogen atom or an aryl group
- the group Rg represents a hydrogen atom or an alkoxyl group
- the groups R to R20 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms, for its use for therapeutic purposes.
- the compound inhibiting the interaction between a Grb14 protein and an insulin receptor for its use for therapeutic purposes, is chosen from the group consisting of compounds belonging to the family of sulphonamide isoxazoles of formula (I), their salts, solvates and / or diastereoisomers
- the group R 1 represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms
- R2, R3, R4 and R5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms;
- the compound of general formula (I) is in trans configuration.
- the groups R2 and R3 represent a hydrogen atom.
- the groups R4 and R5 represent a methyl group.
- the group R 1 represents a linear or branched chain saturated alkyl group containing up to 5 carbon atoms, preferably a linear or branched chain saturated alkyl group. containing up to 3 carbon atoms.
- the group R 1 represents a linear-chain saturated alkyl group containing up to 5 carbon atoms, and even more preferably up to 3 carbon atoms. carbon.
- the inhibiting compound is selected from the group consisting of compounds of formula (Ia) or of formula (Ib):
- the compound inhibiting the interaction between a Grb14 protein and an insulin receptor for its use for therapeutic purposes, is selected from the group consisting of compounds belonging to the dioxothioxotetrahydro-pyrimidinylidene family of formula (II), their salts, solvates, and / or diastereoisomers
- the group Re represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms or a - (C 1 -C 5 alkyl) aryl group, said aryl being substituted by one or more groups chosen from groups following: -C0 2 Rn, COR12, -OC (0) R 3, -S (0) R 4, -OR 15, -SRie, -SO2R17, -CONRi 8 R 9,
- the group R 7 represents a hydrogen atom or a carboxyl group
- the group Re represents a hydrogen atom or an aryl group
- the group Rg represents a hydrogen atom or an alkoxyl group
- the groups R to R20 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms.
- the compound of general formula (II) is in the cis configuration.
- Re represents a linear or branched, preferably saturated, chain alkyl group containing up to 5 carbon atoms. More preferably, in this inhibiting compound of formula (II), Re represents a saturated linear chain alkyl group containing up to 5 carbon atoms. Even more preferably, in this inhibiting compound of formula (II), Re represents a saturated linear chain alkyl group containing up to 3 carbon atoms.
- Re represents a - (C 1 -C 5) alkylaryl group, said aryl being substituted with one or more groups, preferably a group, chosen from groups following: -CO2R11, COR12, -OC (O) R13, -S (O) R14, -OR15, -SR18, -SO2R17, -CONR18R19, -OCO2R20.
- Re represents a benzyl group, substituted with a group chosen from the following groups: -CO2R11, -COR12, -OC (O) R13, -S (O) R14 , - SO2R17.
- the groups R to R20 being as defined above.
- Re represents a benzyl group, substituted with a carboxyl group.
- the inhibiting compound according to the invention is chosen from the group consisting of the compounds of formula (IIa), their salts and / or their solvates,
- the Rio group represents a carboxylic group.
- the alkoxyl group of the Rg group is selected from methoxyl or ethoxyl.
- the group R 7 represents a hydrogen atom when the group Re represents an aryl group.
- the group Re represents a hydrogen atom or a phenyl group.
- the group Re represents a phenyl group.
- the inhibiting compound according to the invention is chosen from the group consisting of compounds of formula (Mb), their salts and / or their solvates,
- the group Re represents a linear or branched chain alkyl group containing up to 5 carbon atoms, or a - (C 1 -C 5) alkyl - aryl group, substituted by a carboxyl group, and
- the group R 7 represents a hydrogen atom or a carboxyl group.
- the inhibiting compound is selected from the group consisting of compounds of formula (II), (IId), (Ile) or (IIf) .
- the invention also relates to a pharmaceutical composition comprising at least one inhibiting compound of formula (I) or formula (II) as defined above for its use for therapeutic purposes.
- the present invention also relates to a pharmaceutical composition comprising at least one inhibiting compound of formula (I) or of formula (II) as defined above and at least one pharmaceutically acceptable excipient for its use for therapeutic purposes.
- compositions according to the invention may be formulated especially for an oral or parenteral administration, comprising the subcutaneous route, the intravenous route and the intramuscular route, preferably for oral administration, said compositions for mammals, including humans.
- the pharmaceutical composition may, for example, be administered orally by means of tablets and capsules.
- the inhibitor compound according to the invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
- a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
- the tablets may be coated with sucrose or other suitable materials, or they may be treated to have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.
- the preparation in capsules is obtained by mixing the inhibiting compound according to the invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
- the present invention relates to the inhibiting compound of general formula (I) or (II) as defined above, or a pharmaceutical composition according to the present invention, for use in the treatment of insulin resistance.
- this inhibitor compound according to the invention is particularly suitable for its use as an insulin sensitizer.
- the present invention also relates to the inhibiting compound of general formula (I) or (II) as defined above, or a pharmaceutical composition according to the present invention, for use in the prevention or treatment of a pathology. associated with insulin resistance.
- the present invention relates to a method of treating insulin resistance comprising the administration to a subject of a pharmaceutically effective amount of an inhibiting compound of general formula (I) or (II) as defined above or a pharmaceutical composition according to the present invention.
- the present invention also relates to a method for preventing or treating a pathology associated with insulin resistance comprising the administration to a subject of a pharmaceutically effective amount of an inhibiting compound of general formula (I) or ( II) as defined above or a pharmaceutical composition according to the present invention.
- the present invention also relates to the use of an inhibitory compound of general formula (I) or (II) as defined above, for the manufacture of a medicament for the treatment of insulin resistance.
- the present invention also relates to the use of an inhibiting compound of general formula (I) or (II) as defined above, for the manufacture of a medicament for the prevention or treatment of a pathology associated with insulin resistance.
- the pathology associated with insulin resistance may preferably be selected from: the metabolic syndrome, polycystic ovary syndrome, obesity, pre-gestational diabetes, type 2 diabetes mellitus, hyperglycemia, lipodystrophy, diabetic nephropathy or cardiovascular complications such as arterial hypertension, diabetic microangiopathy (including diabetic neuropathy and diabetic retinopathy), or diabetic macroangiopathy. More preferably, the pathology associated with insulin resistance may be preferably selected from: obesity, type 2 diabetes, metabolic syndrome and hyperglycemia. Even more preferably, the pathology associated with insulin resistance may be preferably selected from: obesity, type 2 diabetes and hyperglycemia.
- the inhibiting compound according to the invention can be administered in unit dosage forms of administration, in admixture with conventional pharmaceutical carriers, to animals or to mammals, preferentially humans.
- the inhibiting compound of the invention as an active ingredient can be formulated at doses of between 1 and 500 mg, preferably between 25 mg and 250 mg, more preferably 50 mg and 150 mg in galenic forms. allowing a single dose, twice a day in equal doses, or even a desired dose of divided doses throughout the day (eg, but not only, in relation to meals).
- the dose administered per day is advantageously between 50 mg and 500 mg, preferably between 100 mg and 200 mg.
- the dose administered may also be indicated per unit of body weight of the patient to be treated, which is particularly relevant in the treatment of a person whose body mass is out of the norm.
- the inhibiting compound of the invention as an active ingredient can be administered at daily doses of between 1 and 40 mg / kg, preferably between 1 and 20 mg / kg, or even between 1 and 10 mg / kg. It may be necessary to use doses outside these ranges as defined above as determined by those skilled in the art.
- the administration of the inhibitor compound according to the invention may be carried out at least one dose per day.
- the administration of the active ingredient may be performed at least once a week, for example twice a week.
- the treatment of insulin resistance or the prevention and treatment of a pathology associated with insulin resistance by the administration of the inhibitory compound according to the invention may be carried out for a period of between 1 month and 96 months, preferably for a period of one month. duration between 6 months and 72 months, preferably for a period of between 1 2 months and 48 months.
- the treatment of insulin resistance or the prevention and treatment of a pathology associated with insulin resistance by the administration of the active ingredient can also be prolonged over longer periods.
- compositions according to the invention may further comprise at least one other active ingredient, such as an active compound for the treatment of diabetes and more particularly acting as an activator of secretion.
- active ingredient such as an active compound for the treatment of diabetes and more particularly acting as an activator of secretion.
- insulin insulin sensitizer, potentiator of the effects of insulin and / or inhibitor of digestive absorption of carbohydrates.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- At least one other active ingredient such as an antidiabetic agent, preferably as a combination product for simultaneous, joint or separate, or sequential use.
- the pharmaceutical composition according to the present invention may thus further comprise at least one other active ingredient chosen from: sulfonylureas, biguanides such as metformin, thiazolidinediones, GLP1 analogs such as exenatide or liraglutide, dipeptidyl peptidase-4 inhibitors such as gliptin, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin or alogliptin, alpha-glucosidase inhibitors, glinides, fibrates, or inhibitors of SGLT2 such as canaglifozine.
- active ingredient chosen from: sulfonylureas, biguanides such as metformin, thiazolidinediones, GLP1 analogs such as exenatide or liraglutide, dipeptidyl peptidase-4 inhibitors such as gliptin, sitaglip
- Sulfonylureas are active ingredients used in the treatment of type 2 diabetes. They act by increasing the release of insulin by the beta cells of the pancreas.
- the sulphonylureas which may be used in combination with the inhibiting compound according to the invention may be more particularly selected from the following compounds: acetohexamide (968-81-0), carbutamide (339-43-5), chlorpropamide (94-20-2) ), glibenclamide (10238-21 -8), glibornuride (26944-48-9), glipizide (29094-61 -9), glimepiride (93479-97-1), gliclazide (21 187-98-4), gliquidone ( 33342-05-1), glisentide (32797-92-5), glyclopyramide (631-27-6), tolbutamide (64-77-7) and tolazamide (1,156-19-0).
- Biguanides are active ingredients with oral antihyperglycemic properties used in the treatment of type 2 diabetes.
- the biguanides that can be used in combination with the inhibiting compound according to the invention may be more particularly selected from the following compounds: buformin (1,190-53-0), metformin (657-24-9 or 11-15-70-4) and phenformin (834-28-6).
- Thiazolidinediones or glitazones are active ingredients for reducing the level of sugar in the blood and are used in the treatment of type 2 diabetes.
- the thiazolidinediones may be used in combination with the inhibitor compound according to the invention may be more particularly selected from the following compounds: rosiglitazone (122320-73-4 or 302543-62-0 or 155141 -29-0 or 397263-60-4) and pioglitazone (1 1 1025-46-8 or 1 12529-15- 4).
- Glucagon-like peptide-1 (GLP1) analogues promote the proliferation of ⁇ -cells, inhibit apoptosis of ⁇ -cells and are used in the treatment of type 2 diabetes.
- GLP1 analogues can be used in combination with the compound inhibitor according to the invention may be more particularly selected from the following compounds: exenatide (141758-74-9) and liraglutide (204656-20-2).
- Inhibitors of dipeptidyl peptidase-4 allow an increase in the secretion of insulin, a decrease in the secretion of glucagon, and are thus used in the treatment of type 2 diabetes.
- the inhibitors of dipeptidyl peptidase-4 which may be used in combination with the inhibiting compound according to the invention may be more particularly selected from the following compounds: alogliptin (850649-62-6), sitagliptin (654671 -78-0), vildagliptin (274901 -16-5), saxagliptin (361442-04-8), linagliptin (668270-12-0), gemigliptin (91 1637-19-9), berberine (2086-83-1 or 633-65-8 or 633-66-9) and dutogliptin (852329-66-9).
- the alpha-glucosidase inhibitors reduce postprandial hyperglycemia and are thus used in the treatment of type 2 diabetes.
- the alpha-glucosidase inhibitors can be used in combination with the inhibitory compound according to the invention.
- the invention may be more particularly selected from the following compounds: acarbose (56180-94-0), miglitol (72432-03-2), and voglibose (83480-29-9).
- the inhibitors of SGLT2 improve insulin sensitivity and ⁇ -cell function.
- the SGLT2 inhibitors that can be used in combination with the inhibiting compound according to the invention may be more particularly selected from the following compounds: canaglifozine (842133-18-0). dapagliflozin (461432-26-8), ipragliflozin (761423-87-4), tofogliflozin (1201913-82-7 or 903565-83-3) and empagliflozin (864070-44-0).
- Glinides improve the secretion of insulin and are used in the treatment of type 2 diabetes.
- the glinides that can be used in combination with the inhibitor compound according to the invention may be more particularly selected from the following compounds: 145375-43-5), nateglinide (105816-04-4), and repaglinide (135062-02-1).
- Fibrates are lipid-lowering compounds.
- the fibrates that can be used in combination with the inhibitor compound according to the invention may be more particularly selected from the following compounds: bezafibrate (41859-67-0), ciprofibrate (52214-84-3), clof ibrate (637-07- 0 or 882-09-7 or 39087-48-4 or 14613-30-0), fenofibrate (49562-28-9 or 42017-89-0 or 856676-23-8) and gemfibrozil (25812-30-0) .
- the pharmaceutical composition according to the invention further comprises at least one other active ingredient chosen from: metformin, gliptin, and canaglifozine.
- the invention also relates to a pharmaceutical composition according to the invention, for its use for therapeutic purposes in a subject subjected to insulin therapy said insulin therapy comprising the administration of insulin or an insulin analogue.
- the insulin analogue may for example be a modified insulin so as to change the speed of its absorption by the subject.
- the commercial products are for example Lispro, Aspart, Glulisine, Detemir, Degludec and Glargine.
- the present invention also relates to a method for treating insulin resistance, and more particularly to preventing or treating a pathology associated with insulin resistance, comprising administering to a subject in need of a pharmaceutically effective amount. effective of the pharmaceutical composition as defined above.
- the present invention also relates to the use of the pharmaceutical composition as defined above, for the manufacture of a medicament for the treatment of insulin resistance.
- the present invention also relates to the use of the pharmaceutical composition as defined above, for the manufacture of a medicament for the prevention or treatment of a pathology associated with insulin resistance.
- the invention relates to a process for the synthesis of a compound of formula (I) as defined above and including the preferred embodiments. Said method comprising a step of condensation of a sulphonamide of formula (V)
- the groups FU and R5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched chain alkyl group containing up to 5 carbon atoms; with an acrylic acid derivative of formula (IV)
- the group R 1 represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms
- the groups R2 and R3 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms.
- the acrylic acid derivative of formula (IV) can be easily purchased commercially or be synthesized from the general knowledge of those skilled in the art or from the teachings of Pontiki et al. (201 1).
- the method of synthesis according to the invention may comprise a preliminary step of condensation of an aldehyde of formula (III)
- the group R 1 represents a linear, cyclic or branched alkyl group containing up to 5 carbon atoms
- the groups R2 and R3 are identical or different and represent a hydrogen atom or a linear, cyclic or branched alkyl group containing up to 5 carbon atoms; with a malonic acid in the presence of pyridine and piperidine.
- the peptide coupling reagent is selected from HATU (1 - [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate) and Ghosez's reagent (1-chloro-N, N, 2-trimethylpropenylamine).
- the coupling reagent may further be used in combination with DIPEA (A / -ethyl- / V- (propan-2-yl) propan-2-amine).
- the sulphonamide condensation step of formula (V) with the acrylic acid derivative of formula (IV) is carried out in the presence of DMF (dimethylformamide) or DCM (dichloromethane), more preferably in the presence of DMF.
- DMF dimethylformamide
- DCM diichloromethane
- the sulphonamide condensation step of formula (V) with the acrylic acid derivative of formula (IV) comprises a microwave heating and irradiation step, for example at 70 ° C. C and 40 W.
- DCM Dichloromethane DIPEA: ⁇ /, / V-Diisopropylethylamine
- HATU 1 Bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate
- the first optional step consists in converting an aldehyde of formula (III) such as 5-methyl-2-furfuraldehyde into an acrylic acid derivative of formula (IV) such as (E) -acid.
- an aldehyde of formula (III) such as 5-methyl-2-furfuraldehyde
- an acrylic acid derivative of formula (IV) such as (E) -acid.
- 3- 5-methylfuran-2-yl) acrylic acid.
- This transformation has already been described in the literature (Pontiki et al., 201 1). Briefly, (E) -3- (5-methylfuran-2-yl) acrylic acid was obtained by condensation of 5-methyl-2-furfuraldehyde with malonic acid in the presence of pyridine and piperidine.
- the second step consists in the condensation of a sulphonamide of formula (V) such as 4-amino-N- (3,4-dimethyl-1,2-oxazol-5-yl) benzenesulfonamide (sulfisoxazole) with an acrylic acid derivative of formula (IV) such as (E) -3- (5-methylfuran-2-yl) acrylic acid, in the presence of a peptide coupling reagent.
- a sulphonamide of formula (V) such as 4-amino-N- (3,4-dimethyl-1,2-oxazol-5-yl) benzenesulfonamide (sulfisoxazole)
- an acrylic acid derivative of formula (IV) such as (E) -3- (5-methylfuran-2-yl) acrylic acid
- the aqueous extract is acidified with 6M HCl (6 mL) to acidic pH.
- the precipitate thus formed was filtered through Buchner, rinsed with distilled water (2 x 5 mL) and dried at 40 ° C for 6 h to give the compound of formula (la) (89 mg, 44%) as a a light yellow solid.
- HEK293T cells were transfected with a vector coding for the insulin receptor fused to luciferase (IR-Luc). Before lysis, cells transfected with IR-Luc were stimulated or not with 100 nM insulin for 10 minutes. The IR-Luc lysates were recovered and then purified on Sepharose beads coupled to wheat germ lectin (WGL for Wheat Germ Lectin). The IR-Luc receptors were then eluted and frozen in liquid nitrogen before being stored at -80 ° C.
- HEK293T cells were transfected with either a vector encoding Grb14 protein fused to YFP (Grb14-YFP) or the empty pcDNA3 plasmid. Cells transfected with Grb14-YFP or with the empty pcDNA3 plasmid were lysed 48 h after transfection. After centrifugation, the lysates are recovered and frozen at -80 ° C.
- the insulin receptors (IR-Luc) partially purified from cells stimulated or not with insulin were incubated for 20 minutes with the inhibitor compounds according to the invention suspended in DMSO.
- the cell extracts from cells transfected with Grb14-YFP (or the empty pcDNA3 plasmid) were then added and after 40 minutes of incubation, coelenterazine was added and the BRET reading was initiated.
- the results are expressed as a percentage of the BRET signal obtained in the presence of the tested molecules with respect to the BRET signal of the DMSO control.
- the compounds according to the invention induce a decrease of the BRET signal between the insulin receptor and the Grb14 protein.
- the compound of formula Ile decreases by 25% the BRET signal between the insulin receptor and the Grb14 protein.
- the compound of formula (Ia) induces a significant decrease of 60% in BRET IR-Grb14 at 50 ⁇ M.
- the inhibitory effect of the compounds according to the invention on the IR-Grb14 interaction was confirmed in co-immunoprecipitation experiments in acellular system.
- the IR-Luc extracts stimulated or not by insulin were preincubated for 20 minutes in the absence or in the presence of 50 ⁇ l of the compound according to the invention before being incubated with the cell extract containing the fusion protein.
- Grb14-YFP for 40 minutes. YFP-directed immunoprecipitation allows the Western blot to analyze the amount of receptor that has remained associated with the Grb14 protein.
- HEK 293T cells co-transfected with a construct bearing only the tyrosine kinase domain of the luciferase-fused receptor (IRTK48-RLuc) and the Grb14 protein fused to the YFP were incubated for 4 hours in the presence of compounds according to the invention.
- the insulin receptor tyrosine kinase domain spontaneously autophosphorylates, so it is not necessary to add insulin to stimulate the IRTK-Grb14 interaction.
- the Western blot analysis of the amount of IRTK48-Rluc co-precipitated with the Grb14 proteins shows that the amount of tyrosine kinase domain of the insulin receptor coimmunized with the Grb14 protein is decreased by 75% by the compound of formula (Ia), 50 ⁇ l.
- This result indicates that the compound of formula (Ia) enters the cells and decreases the interaction between the insulin receptor kinase domain and the Grb14 protein.
- the compound of formula (Ia) therefore acts well at the insulin receptor tyrosine kinase domain, the only part of the receptor present in the construct used for this experiment. This confirms that the compounds according to the invention inhibit the IR-Grb14 interaction by acting specifically on the kinase domain of the insulin receptor.
- FIG. 3B having densitometric quantification of the signals revealed, shows that the compound of formula (Ia) does not modify the amounts of tyrosine kinase domain of the insulin receptor coimmunized with the Grb10 protein.
- the compound of formula (Ia) seems specific for the IRTK-Grb14 interaction, since it does not inhibit the IRTK-Grb10 interaction.
- HEK293T cells were cultured for 72 h at different concentrations of serum (0.1%, 1%, 10%). ), in the absence or in the presence of compound of formula (la) (50 or 100 ⁇ ).
- the fluorescence of the cells was measured before and after treatment with a reagent containing resazurin. Knowing that the intensity of the fluorescence is correlated with the number of living cells, the growth of the cells is estimated by relating the fluorescence measured at 72 h of treatment to that measured at tO. The presence of serum promotes cell growth. Thus, after 72 hours, the cell population is increased from 7 times to 0.1% serum and 10 times to 1 or 10% serum.
- the compound of formula (la) at 50 ⁇ and 100 ⁇ does not modify the cell growth rate.
- mice were treated daily either by gavage with 30 mg / kg / day of compound of formula (Ia) diluted in 0.5% carboxymethylcellulose; either by intraperitoneal injection with 30 mg / kg / day of compound of formula (Ia) diluted in DMSO, or with DMSO alone, for a period of 15 days.
- mice Before the start of the treatments, the mice had a similar body weight. After 12 days of treatment, no difference in weight gain was observed between the different groups, regardless of the treatment. Moreover, regardless of the method of administration of the compound according to the invention, it is possible to observe a decrease in the glycemia measured in the post-absorptive state. Finally, no difference in the appearance of the liver was observed in these mice.
- the compound of formula (Ia) according to the invention therefore has no detectable toxic effect.
- HEK293T cells are transfected with plasmids allowing, on the one hand, the expression of the PH domain. (Pleckstrin Homology) of the Akt protein that has been fused to luciferase and on the other hand a membrane targeting sequence that has been fused to the YFP protein.
- Akt PH domain is recruited to the membrane by PIP3
- energy transfer between the luciferase that is coupled to the Akt PH domain and the membrane YFP protein takes place.
- the measured BRET signal is a control of PIP3 production at the membrane and is a reflection of the activation of the PI-3 kinase / Akt pathway in real time on cells.
- insulin induces a rapid increase in the BRET signal (BRET delta of about 100).
- the compound of formula (la) (50 ⁇ l) increases the recruitment of the Akt protein to the membrane in the absence (BRET delta of approximately 86) and in the presence (BRET delta of approximately 121) of 5 nM insulin. .
- the effect of the compound of formula (Ia), in the absence of insulin is detectable as early as 5 ⁇ l, with a significant increase of the BRET signal at 10 ⁇ l (results not shown). This effect is also observed for the other inhibiting compounds according to the invention as shown in Table 3.
- the effect of the comparative compounds of formula (IVa) and of formula (Va) used in the synthesis of the compound of formula (Ia) on the PI3K / Akt pathway was tested in the presence of 5 nM insulin.
- the compounds of formula (IVa) and formula (Va) (added separately or simultaneously) have no effect on the recruitment of Akt kinase to the membrane in the absence of the hormone.
- the compound of formula (Va) also has no effect on the production of PIP3 at the membrane.
- the effect of the compound of formula (Ia) on the increase in the production of PIP3 at the membrane was not found in all cellular systems. Indeed, in MCF7 cells (mammary tumor cells) which overexpress the IGF-1 receptor relative to the insulin receptor (Zhang et al., 2007), the compound of formula (la) (50 ⁇ l) has no effect on membrane production of PIP3 (in the absence and presence of 100 nM insulin). This suggests that the compound of formula (Ia) does not stimulate the PI3K / Akt pathway in cancer cells that overexpress the IGF-1 receptor. Finally, the compounds according to the invention increase the Ras / Raf interaction whether the cells are stimulated or not by insulin (results not shown).
- the compounds according to the invention thus induce activation of PI3K / Akt pathways. These compounds potentiate the effect of insulin, but also have an activating effect in the absence of the hormone. In addition, the effect of the compound of formula (Ia) on the activation of the PI3K / Akt pathway is significant from 10 ⁇ . Finally, the effect of the compound of formula (Ia) on the activation of the PI3K / Akt pathway depends on the TK activity of the insulin receptor, proving a specificity of action. 6.2: Expression of the genes for gluconeogenesis
- mouse hepatocytes in primary culture were pre-incubated with 10 nM glucagon.
- glucagon strongly induces the expression of the key gluconeogenesis genes PEPCK and G6Pase, and the addition of insulin at 1 nM inhibits by approximately 60 to 70%. expression of these genes.
- the compound of formula (Ia) induces a significant decrease of about 20% in the expression of PEPCK and glucagon-induced G6Pase.
- the compounds according to the invention also reduce, even in the absence of insulin, the expression of glucagon-induced gluconeogenesis genes in hepatocytes in primary culture.
- mouse hepatocytes in primary culture are cultured in the presence of 5 mM glucose (G5) or 25 mM glucose (G25) and 10 nM insulin for 24 h.
- the relative quantification of the mRNAs is carried out by RT-qPCR and the values are related to the quantification of the 18S gene of the same sample in order to normalize the results.
- G251 G25, with 10 nM insulin
- a 60% increase in the expression of the messenger RNA of SREBP-1 c is observed, as well as an increase in the expression of its target genes ACC (of 650%), FAS (of 150%) and SCD1 (of 160%).
- NCEP National Cholesterol Education Program
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1752287A FR3063903B1 (fr) | 2017-03-20 | 2017-03-20 | Nouveaux composes, compositions et methodes pour le traitement de la resistance a l’insuline |
PCT/EP2018/056931 WO2018172306A1 (fr) | 2017-03-20 | 2018-03-20 | Nouveaux composes, compositions et methodes pour le traitement de la resistance a l'insuline |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3600296A1 true EP3600296A1 (fr) | 2020-02-05 |
Family
ID=59153044
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP18710891.5A Withdrawn EP3600296A1 (fr) | 2017-03-20 | 2018-03-20 | Nouveaux composes, compositions et methodes pour le traitement de la resistance a l'insuline |
Country Status (4)
Country | Link |
---|---|
US (1) | US11020378B2 (fr) |
EP (1) | EP3600296A1 (fr) |
FR (1) | FR3063903B1 (fr) |
WO (1) | WO2018172306A1 (fr) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1145822A (en) | 1965-03-10 | 1969-03-19 | May & Baker Ltd | Thiazole derivatives |
FR2790956B1 (fr) | 1999-03-15 | 2003-05-23 | Centre Nat Rech Scient | UTILISATION DE LA PROTEINE Grb14 ET DES PROTEINES ADAPTATRICES HOMOLOGUES COMME OUTIL DE CRIBLAGE DE MOLECULES DESTINEES AU TRAITEMENT DES MALADIES LIEES A L'INSULINE |
KR101411838B1 (ko) * | 2011-02-09 | 2014-06-27 | 부산대학교 산학협력단 | 피부미백, 항산화 및 ppar 활성을 갖는 신규 화합물 및 이의 의학적 용도 |
US11311543B2 (en) * | 2016-05-27 | 2022-04-26 | Yale University | Compositions and methods for inhibiting PTPN22 |
-
2017
- 2017-03-20 FR FR1752287A patent/FR3063903B1/fr not_active Expired - Fee Related
-
2018
- 2018-03-20 WO PCT/EP2018/056931 patent/WO2018172306A1/fr unknown
- 2018-03-20 US US16/496,111 patent/US11020378B2/en active Active
- 2018-03-20 EP EP18710891.5A patent/EP3600296A1/fr not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
US11020378B2 (en) | 2021-06-01 |
FR3063903A1 (fr) | 2018-09-21 |
WO2018172306A1 (fr) | 2018-09-27 |
FR3063903B1 (fr) | 2019-04-12 |
US20200030297A1 (en) | 2020-01-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2002314944B2 (en) | Isoxazoline compounds having MIF antagonist activity | |
Liu et al. | Cyclobutane derivatives as novel nonpeptidic small molecule agonists of glucagon-like peptide-1 receptor | |
AU2002314944A1 (en) | Isoxazoline compounds having MIF antagonist activity | |
WO2010056992A1 (fr) | Procédés de prévention et de traitement de maladies de faible masse osseuse | |
WO2018175537A1 (fr) | Inhibition sélective de l'activité gluconéogène | |
US8759364B2 (en) | Methods of treating bone mass diseases | |
EP3280404B1 (fr) | Procédés de sélection d'inhibiteurs sélectifs et non sélectifs des phosphatase | |
WO2015059463A2 (fr) | Bêta-caténine | |
US20210315908A1 (en) | Compositions and methods related to cholic acid 7-sulfate as a treatment for diabetes | |
WO2008055445A1 (fr) | Méthode et composition pour accroître la sensibilité à l'insuline | |
Wu et al. | Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress | |
US8815883B2 (en) | Compounds and methods for inhibiting serotonin synthesis | |
FR2861304A1 (fr) | Modulateurs des canaux cftr | |
EP3600296A1 (fr) | Nouveaux composes, compositions et methodes pour le traitement de la resistance a l'insuline | |
CA2849309C (fr) | Nouveaux composes modulateurs de la voie de signalisation des proteines hedgehog, leurs formes marquees, et applications | |
US9040713B2 (en) | Methods of managing blood sugar levels and compositions related thereto | |
WO2021226447A1 (fr) | Procédés d'induction de sulfotransférase sult2a d'acide biliaire pour le traitement de troubles métaboliques | |
Kumar | Trace amine-associated receptor 1 activation regulates glucose-dependent insulin secretion in pancreatic beta cells in vitro | |
Yesudas et al. | Functional role of sodium glucose transporter in high glucose-mediated angiotensin type 1 receptor downregulation in human proximal tubule cells | |
CN112745319B (zh) | 一类取代三环结构的化合物、其制备方法及用途 | |
TW202228696A (zh) | 稠合雜環類化合物及其製備方法和醫藥用途 | |
CN106860445B (zh) | 血竭素、血竭素衍生物或其可用盐在制备糖尿病药物中的应用 | |
Keyser | Role of T-type calcium channels in basal [calcium (2+)](i) and insulin secretion in pancreatic beta-cells under hypergyclemia | |
Salvatori | New insights into the control of pancreatic islet cell function | |
ERION | QUN DANG*, PAUL D. VAN POELJE AND |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20191003 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20201104 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20221001 |