CN100384430C - 含有葡萄糖重吸收抑制剂和维生素a类-x受体调节剂的联合治疗 - Google Patents
含有葡萄糖重吸收抑制剂和维生素a类-x受体调节剂的联合治疗 Download PDFInfo
- Publication number
- CN100384430C CN100384430C CNB02810482XA CN02810482A CN100384430C CN 100384430 C CN100384430 C CN 100384430C CN B02810482X A CNB02810482X A CN B02810482XA CN 02810482 A CN02810482 A CN 02810482A CN 100384430 C CN100384430 C CN 100384430C
- Authority
- CN
- China
- Prior art keywords
- glucose reabsorption
- glucose
- reabsorption inhibitor
- purposes
- retinoid
- 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.)
- Expired - Lifetime
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 60
- 230000030558 renal glucose absorption Effects 0.000 title claims abstract description 44
- 102000034527 Retinoid X Receptors Human genes 0.000 title claims description 62
- 108010038912 Retinoid X Receptors Proteins 0.000 title claims description 62
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 52
- 238000011282 treatment Methods 0.000 claims abstract description 43
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 26
- -1 α-D-glucopyranosyl Chemical group 0.000 claims description 172
- 150000001875 compounds Chemical class 0.000 claims description 61
- 239000003814 drug Substances 0.000 claims description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 34
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 31
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 24
- 208000024891 symptom Diseases 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 20
- 230000004224 protection Effects 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- GMYFQAHYWIYNES-PFKOEMKTSA-N 3-(1-benzofuran-5-yl)-1-[2-hydroxy-4-methyl-6-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]propan-1-one Chemical compound C=1C(C)=CC(O)=C(C(=O)CCC=2C=C3C=COC3=CC=2)C=1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GMYFQAHYWIYNES-PFKOEMKTSA-N 0.000 claims description 14
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 14
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 10
- 230000004048 modification Effects 0.000 claims description 8
- 238000012986 modification Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000017169 kidney disease Diseases 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 208000017442 Retinal disease Diseases 0.000 claims description 6
- 206010038923 Retinopathy Diseases 0.000 claims description 6
- 201000001119 neuropathy Diseases 0.000 claims description 6
- 230000007823 neuropathy Effects 0.000 claims description 6
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 208000037902 enteropathy Diseases 0.000 claims description 5
- 208000019622 heart disease Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 208000028774 intestinal disease Diseases 0.000 claims description 5
- 208000028867 ischemia Diseases 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 208000002177 Cataract Diseases 0.000 claims description 3
- 238000011161 development Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 2
- 208000001280 Prediabetic State Diseases 0.000 claims description 2
- 238000013329 compounding Methods 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 238000002648 combination therapy Methods 0.000 abstract 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 98
- 239000008103 glucose Substances 0.000 description 69
- 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 67
- 239000002585 base Substances 0.000 description 66
- 102000004877 Insulin Human genes 0.000 description 60
- 108090001061 Insulin Proteins 0.000 description 60
- 239000000556 agonist Substances 0.000 description 55
- 229940125396 insulin Drugs 0.000 description 49
- 229940123464 Thiazolidinedione Drugs 0.000 description 43
- 210000002381 plasma Anatomy 0.000 description 43
- 210000004185 liver Anatomy 0.000 description 38
- NKPYIZCCIFRRRC-USWKJHDZSA-N 3-(1-benzofuran-5-yl)-1-[2-hydroxy-4-methyl-6-[(2r,3r,4s,5s,6s)-3,4,5,6-tetrahydroxyoxan-2-yl]oxyphenyl]propan-1-one Chemical group C=1C(C)=CC(O)=C(C(=O)CCC=2C=C3C=COC3=CC=2)C=1O[C@@H]1O[C@H](O)[C@@H](O)[C@H](O)[C@H]1O NKPYIZCCIFRRRC-USWKJHDZSA-N 0.000 description 32
- 230000000694 effects Effects 0.000 description 31
- 230000037396 body weight Effects 0.000 description 29
- 229940121377 sodium-glucose co-transporter inhibitor Drugs 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 19
- 229940079593 drug Drugs 0.000 description 19
- 125000006239 protecting group Chemical group 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 18
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 17
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) 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)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 17
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 16
- 206010022489 Insulin Resistance Diseases 0.000 description 15
- 239000000890 drug combination Substances 0.000 description 15
- 206010030113 Oedema Diseases 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 125000002252 acyl group Chemical group 0.000 description 12
- 230000003203 everyday effect Effects 0.000 description 12
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 12
- 241000790917 Dioxys <bee> Species 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 229960003105 metformin Drugs 0.000 description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 230000000747 cardiac effect Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 230000002218 hypoglycaemic effect Effects 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 210000002700 urine Anatomy 0.000 description 9
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 8
- 229940126033 PPAR agonist Drugs 0.000 description 8
- 229960002938 bexarotene Drugs 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 201000001421 hyperglycemia Diseases 0.000 description 8
- 229920000609 methyl cellulose Polymers 0.000 description 8
- 239000001923 methylcellulose Substances 0.000 description 8
- 235000010981 methylcellulose Nutrition 0.000 description 8
- 229940103453 novolin Drugs 0.000 description 8
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 8
- 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 8
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 208000013016 Hypoglycemia Diseases 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical group 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 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 7
- 239000003826 tablet Substances 0.000 description 7
- 150000001467 thiazolidinediones Chemical class 0.000 description 7
- 102000014914 Carrier Proteins Human genes 0.000 description 6
- 108010078791 Carrier Proteins Proteins 0.000 description 6
- 206010020880 Hypertrophy Diseases 0.000 description 6
- 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 6
- 241001597008 Nomeidae Species 0.000 description 6
- 108010016731 PPAR gamma Proteins 0.000 description 6
- 102000000536 PPAR gamma Human genes 0.000 description 6
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 6
- 208000004880 Polyuria Diseases 0.000 description 6
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 6
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000001118 alkylidene group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 239000003472 antidiabetic agent Substances 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000008014 freezing Effects 0.000 description 6
- 238000007710 freezing Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 230000001976 improved effect Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 230000010534 mechanism of action Effects 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 231100000572 poisoning Toxicity 0.000 description 6
- 230000000607 poisoning effect Effects 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 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 5
- 206010002091 Anaesthesia Diseases 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- AIRYAONNMGRCGJ-FHFVDXKLSA-N 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)N[C@@H](CCCCN)C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC 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)N[C@@H](CCCCN)C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC AIRYAONNMGRCGJ-FHFVDXKLSA-N 0.000 description 5
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 5
- 208000004930 Fatty Liver Diseases 0.000 description 5
- 206010019708 Hepatic steatosis Diseases 0.000 description 5
- 102000013266 Human Regular Insulin Human genes 0.000 description 5
- 108010090613 Human Regular Insulin Proteins 0.000 description 5
- 108010028924 PPAR alpha Proteins 0.000 description 5
- 102000023984 PPAR alpha Human genes 0.000 description 5
- 239000004743 Polypropylene 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 125000004423 acyloxy group Chemical group 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 230000037005 anaesthesia Effects 0.000 description 5
- 230000003178 anti-diabetic effect Effects 0.000 description 5
- 229940050390 benzoate Drugs 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 229960004365 benzoic acid Drugs 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 208000010706 fatty liver disease Diseases 0.000 description 5
- 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 5
- 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 5
- 230000002641 glycemic effect Effects 0.000 description 5
- 229940103471 humulin Drugs 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 229920001155 polypropylene Polymers 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 231100000240 steatosis hepatitis Toxicity 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- MJAMNJNCEOHYIU-UHFFFAOYSA-N 1,2-oxazolidine-3,4-dione Chemical compound O=C1CONC1=O MJAMNJNCEOHYIU-UHFFFAOYSA-N 0.000 description 4
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 4
- WEDIKSVWBUKTRA-WTKGVUNUSA-N 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)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC 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)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC WEDIKSVWBUKTRA-WTKGVUNUSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 4
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- 108091006277 SLC5A1 Proteins 0.000 description 4
- 108091006269 SLC5A2 Proteins 0.000 description 4
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 4
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 4
- 229940100389 Sulfonylurea Drugs 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 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 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000035619 diuresis Effects 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 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 4
- 235000021588 free fatty acids Nutrition 0.000 description 4
- 150000002303 glucose derivatives Chemical class 0.000 description 4
- 238000005534 hematocrit Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000005217 methyl ethers Chemical class 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 4
- 125000006502 nitrobenzyl group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 108010029667 pramlintide Proteins 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 231100000489 sensitizer Toxicity 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- JRCLCXAVSVCEQC-UHFFFAOYSA-N $l^{1}-oxidanylformaldehyde Chemical compound [O]C=O JRCLCXAVSVCEQC-UHFFFAOYSA-N 0.000 description 3
- SLXTWXQUEZSSTJ-UHFFFAOYSA-N 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]pyridine-3-carboxylic acid Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C1(C=2N=CC(=CC=2)C(O)=O)CC1 SLXTWXQUEZSSTJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 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 3
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 108010057186 Insulin Glargine Proteins 0.000 description 3
- 108010065920 Insulin Lispro Proteins 0.000 description 3
- 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 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- 229960002632 acarbose Drugs 0.000 description 3
- YAJCHEVQCOHZDC-QMMNLEPNSA-N actrapid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@H](C)CC)[C@H](C)CC)[C@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(N)=O)C1=CNC=N1 YAJCHEVQCOHZDC-QMMNLEPNSA-N 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 3
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].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](CC3N=CN=C3)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(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 3
- 239000012055 enteric layer Substances 0.000 description 3
- 229960004666 glucagon Drugs 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 3
- 201000008980 hyperinsulinism Diseases 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229960000367 inositol Drugs 0.000 description 3
- 239000004026 insulin derivative Substances 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 210000004153 islets of langerhan Anatomy 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229920001206 natural gum Polymers 0.000 description 3
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxy-acetic acid Natural products OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 3
- IOUVKUPGCMBWBT-UHFFFAOYSA-N phloridzosid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-UHFFFAOYSA-N 0.000 description 3
- IOUVKUPGCMBWBT-QNDFHXLGSA-N phlorizin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-QNDFHXLGSA-N 0.000 description 3
- 235000019139 phlorizin Nutrition 0.000 description 3
- 229960005095 pioglitazone Drugs 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011808 rodent model Methods 0.000 description 3
- SUFUKZSWUHZXAV-BTJKTKAUSA-N rosiglitazone maleate Chemical compound [H+].[H+].[O-]C(=O)\C=C/C([O-])=O.C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O SUFUKZSWUHZXAV-BTJKTKAUSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 3
- 235000010487 tragacanth Nutrition 0.000 description 3
- 239000000196 tragacanth Substances 0.000 description 3
- 229940116362 tragacanth Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 229960004441 tyrosine Drugs 0.000 description 3
- 229910052720 vanadium Inorganic materials 0.000 description 3
- 229960001729 voglibose Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- OELFLUMRDSZNSF-OFLPRAFFSA-N (2R)-2-[[oxo-(4-propan-2-ylcyclohexyl)methyl]amino]-3-phenylpropanoic acid Chemical compound C1CC(C(C)C)CCC1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-OFLPRAFFSA-N 0.000 description 2
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-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
- CDAISMWEOUEBRE-LKPKBOIGSA-N 1D-chiro-inositol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O CDAISMWEOUEBRE-LKPKBOIGSA-N 0.000 description 2
- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical group FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 description 2
- IHBAVXVTGLANPI-QMMMGPOBSA-N 2-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one Chemical compound CC(C)[C@H](N)C(=O)N1CCCC1 IHBAVXVTGLANPI-QMMMGPOBSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- QBQLYIISSRXYKL-UHFFFAOYSA-N 4-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,2-oxazolidine-3,5-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCOC(C=C1)=CC=C1CC1C(=O)NOC1=O QBQLYIISSRXYKL-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- IETKPTYAGKZLKY-UHFFFAOYSA-N 5-[[4-[(3-methyl-4-oxoquinazolin-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound N=1C2=CC=CC=C2C(=O)N(C)C=1COC(C=C1)=CC=C1CC1SC(=O)NC1=O IETKPTYAGKZLKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102100033367 Appetite-regulating hormone Human genes 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 208000032841 Bulimia Diseases 0.000 description 2
- 206010006550 Bulimia nervosa Diseases 0.000 description 2
- 102000002666 Carnitine O-palmitoyltransferase Human genes 0.000 description 2
- 108010018424 Carnitine O-palmitoyltransferase Proteins 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
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 102100030431 Fatty acid-binding protein, adipocyte Human genes 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 102000001267 GSK3 Human genes 0.000 description 2
- QTQMRBZOBKYXCG-MHZLTWQESA-N GW 1929 Chemical compound N([C@@H](CC1=CC=C(C=C1)OCCN(C)C=1N=CC=CC=1)C(O)=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 QTQMRBZOBKYXCG-MHZLTWQESA-N 0.000 description 2
- GGUVRMBIEPYOKL-WMVCGJOFSA-N GW 409544 Chemical compound C([C@H](NC(/C)=C\C(=O)C=1C=CC=CC=1)C(O)=O)C(C=C1)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 GGUVRMBIEPYOKL-WMVCGJOFSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 108010073961 Insulin Aspart Proteins 0.000 description 2
- 108010089308 Insulin Detemir Proteins 0.000 description 2
- 229940122355 Insulin sensitizer Drugs 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- PMRVFZXOCRHXFE-FMEJWYFOSA-L Kad 1229 Chemical compound [Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 PMRVFZXOCRHXFE-FMEJWYFOSA-L 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- AAKDPDFZMNYDLR-UHFFFAOYSA-N N-methyl deoxynojirimycin Natural products CN1CC(O)C(O)C(O)C1CO AAKDPDFZMNYDLR-UHFFFAOYSA-N 0.000 description 2
- AAKDPDFZMNYDLR-XZBKPIIZSA-N N-methyl-1-deoxynojirimycin Chemical compound CN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO AAKDPDFZMNYDLR-XZBKPIIZSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 2
- 102100023536 Solute carrier family 2, facilitated glucose transporter member 1 Human genes 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WVYIXBYYAHYOIW-UHFFFAOYSA-N TMC-2C Natural products C1=CC=C2C(CC(N)C(=O)N3C(CC4=CC(O)=C(C(=C4C3)O)OC)C(=O)NC(CC(C)CO)C(O)=O)=CNC2=C1 WVYIXBYYAHYOIW-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 206010043458 Thirst Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102000055135 Vasoactive Intestinal Peptide Human genes 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 229960001466 acetohexamide Drugs 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
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 2
- 108010028144 alpha-Glucosidases Proteins 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 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
- 210000001136 chorion Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 208000028208 end stage renal disease Diseases 0.000 description 2
- 201000000523 end stage renal failure Diseases 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2r,3r,4r,5s)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- ZZCHHVUQYRMYLW-HKBQPEDESA-N farglitazar Chemical compound N([C@@H](CC1=CC=C(C=C1)OCCC=1N=C(OC=1C)C=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 ZZCHHVUQYRMYLW-HKBQPEDESA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 108010077689 gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide Proteins 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960004580 glibenclamide Drugs 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
- 229960001381 glipizide Drugs 0.000 description 2
- 229960003468 gliquidone Drugs 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
- 229950008402 glisentide Drugs 0.000 description 2
- GZKDXUIWCNCNBJ-UHFFFAOYSA-N glisolamide Chemical compound O1C(C)=CC(C(=O)NCCC=2C=CC(=CC=2)S(=O)(=O)NC(=O)NC2CCCCC2)=N1 GZKDXUIWCNCNBJ-UHFFFAOYSA-N 0.000 description 2
- 229950005319 glisolamide Drugs 0.000 description 2
- 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 2
- 208000018914 glucose metabolism disease Diseases 0.000 description 2
- 230000006377 glucose transport Effects 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229950004152 insulin human Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 235000019136 lipoic acid Nutrition 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 229960001110 miglitol Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 229960000698 nateglinide Drugs 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229940127017 oral antidiabetic Drugs 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940044115 phlorhizin Drugs 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 229940067626 phosphatidylinositols Drugs 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229960003611 pramlintide Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- CRPGRUONUFDYBG-UHFFFAOYSA-N risarestat Chemical compound C1=C(OCC)C(OCCCCC)=CC=C1C1C(=O)NC(=O)S1 CRPGRUONUFDYBG-UHFFFAOYSA-N 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000005728 strengthening Methods 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940099419 targretin Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229960002277 tolazamide Drugs 0.000 description 2
- 229960001641 troglitazone Drugs 0.000 description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BOOOLEGQBVUTKC-NVQSDHBMSA-N (2e,4e)-3-methyl-5-[(1s,2s)-2-methyl-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)cyclopropyl]penta-2,4-dienoic acid Chemical compound OC(=O)\C=C(/C)\C=C\[C@@H]1C[C@]1(C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 BOOOLEGQBVUTKC-NVQSDHBMSA-N 0.000 description 1
- FOPYPXYFIMTSMM-PKPIPKONSA-N (2r)-2-(dithiolan-3-yl)pentanoic acid Chemical compound CCC[C@H](C(O)=O)C1CCSS1 FOPYPXYFIMTSMM-PKPIPKONSA-N 0.000 description 1
- WMUIIGVAWPWQAW-XMMPIXPASA-N (2r)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid Chemical compound C1=CC(C[C@@H](OCC)C(O)=O)=CC=C1OCCN1C2=CC=CC=C2OC2=CC=CC=C21 WMUIIGVAWPWQAW-XMMPIXPASA-N 0.000 description 1
- NDVRKEKNSBMTAX-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;phosphoric acid Chemical compound OP(O)(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O NDVRKEKNSBMTAX-BTVCFUMJSA-N 0.000 description 1
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 1
- JTBVPIHWMWILJU-MHZLTWQESA-N (2s)-2-(2-acetylanilino)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoic acid Chemical compound CC(=O)C1=CC=CC=C1N[C@H](C(O)=O)CC(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 JTBVPIHWMWILJU-MHZLTWQESA-N 0.000 description 1
- QNDFBOXBUCDYNZ-NRFANRHFSA-N (2s)-2-ethoxy-3-[4-[2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]ethoxy]phenyl]propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(NC(=O)OC(C)(C)C)C=C1 QNDFBOXBUCDYNZ-NRFANRHFSA-N 0.000 description 1
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- JXHFHOSKMYEEHT-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione;hydrochloride Chemical compound Cl.O=C1CSC(=O)N1 JXHFHOSKMYEEHT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- ZSTYYFFNSBKYLC-UHFFFAOYSA-N 2-[2-[(e)-(aminohydrazinylidene)methyl]hydrazinyl]acetic acid Chemical compound NNN=CNNCC(O)=O ZSTYYFFNSBKYLC-UHFFFAOYSA-N 0.000 description 1
- KCEFVYIWOQSJCH-LMOVPXPDSA-N 2-[4-[2-[[(2r)-2-hydroxy-2-phenylethyl]amino]ethoxy]phenyl]acetic acid;hydrochloride Chemical compound Cl.C([C@H](O)C=1C=CC=CC=1)NCCOC1=CC=C(CC(O)=O)C=C1 KCEFVYIWOQSJCH-LMOVPXPDSA-N 0.000 description 1
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 1
- ASWYZRRXMGAWGN-UHFFFAOYSA-N 2-[[2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl]amino]ethyl 4-[2-[[2-(9h-fluoren-9-yl)acetyl]amino]ethyl]benzoate Chemical compound C=1C=C(CCNC(=O)CC2C3=CC=CC=C3C3=CC=CC=C32)C=CC=1C(=O)OCCNCC(OC)C1=CC=CC(C(F)(F)F)=C1 ASWYZRRXMGAWGN-UHFFFAOYSA-N 0.000 description 1
- JELDFLOBXROBFH-UHFFFAOYSA-N 2-[[4-[[2-(2h-tetrazol-5-ylmethyl)phenyl]methoxy]phenoxy]methyl]quinoline Chemical compound C=1C=C2C=CC=CC2=NC=1COC(C=C1)=CC=C1OCC1=CC=CC=C1CC=1N=NNN=1 JELDFLOBXROBFH-UHFFFAOYSA-N 0.000 description 1
- GURGSGFLDQWKEN-UHFFFAOYSA-N 2-[amino-[(aminohydrazinylidene)methyl]amino]acetic acid Chemical compound NNN=CN(N)CC(O)=O GURGSGFLDQWKEN-UHFFFAOYSA-N 0.000 description 1
- BJBCSGQLZQGGIQ-QGZVFWFLSA-N 2-acetamidoethyl (2r)-2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetate Chemical compound O([C@@H](C(=O)OCCNC(=O)C)C=1C=CC(Cl)=CC=1)C1=CC=CC(C(F)(F)F)=C1 BJBCSGQLZQGGIQ-QGZVFWFLSA-N 0.000 description 1
- CCTREOMTIFSZAU-OGFXRTJISA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;5-[(3r)-dithiolan-3-yl]pentanoic acid Chemical compound OCC(N)(CO)CO.OC(=O)CCCC[C@@H]1CCSS1 CCTREOMTIFSZAU-OGFXRTJISA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- CZMRCDWAGMRECN-UHFFFAOYSA-N 2-{[3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HMLWNNMYODLLJO-UHFFFAOYSA-N 3-methyl-1,3-thiazolidine-2,4-dione Chemical compound CN1C(=O)CSC1=O HMLWNNMYODLLJO-UHFFFAOYSA-N 0.000 description 1
- JOWMTYWOBJALGB-UHFFFAOYSA-N 4-(4-methylcyclohexyl)-4-oxobutanoic acid Chemical compound CC1CCC(C(=O)CCC(O)=O)CC1 JOWMTYWOBJALGB-UHFFFAOYSA-N 0.000 description 1
- LGSOKZOQANLOEU-UHFFFAOYSA-N 4-[2-(2,4-dioxo-1,3-thiazolidin-5-yl)ethoxy]benzonitrile Chemical compound S1C(=O)NC(=O)C1CCOC1=CC=C(C#N)C=C1 LGSOKZOQANLOEU-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 1
- AZKFGOQRYCSQPK-UHFFFAOYSA-N 5-[(7-phenylmethoxyquinolin-3-yl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CN=C(C=C(OCC=2C=CC=CC=2)C=C2)C2=C1 AZKFGOQRYCSQPK-UHFFFAOYSA-N 0.000 description 1
- FQCUYGFIIAZMLU-UHFFFAOYSA-N 5-[[2-(naphthalen-2-ylmethyl)-1,3-benzoxazol-5-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(OC(CC=2C=C3C=CC=CC3=CC=2)=N2)C2=C1 FQCUYGFIIAZMLU-UHFFFAOYSA-N 0.000 description 1
- HAAXAFNSRADSMK-UHFFFAOYSA-N 5-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1-benzothiophen-7-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCOC(C=1C=CSC=11)=CC=C1CC1SC(=O)NC1=O HAAXAFNSRADSMK-UHFFFAOYSA-N 0.000 description 1
- YVQKIDLSVHRBGZ-UHFFFAOYSA-N 5-[[4-[2-hydroxy-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1C(O)COC(C=C1)=CC=C1CC1SC(=O)NC1=O YVQKIDLSVHRBGZ-UHFFFAOYSA-N 0.000 description 1
- BDIDRHMZXLEMIZ-UHFFFAOYSA-N 6-(hydroxymethyl)-7-oxabicyclo[4.1.0]heptane-3,4,5-triol Chemical compound C1C(O)C(O)C(O)C2(CO)C1O2 BDIDRHMZXLEMIZ-UHFFFAOYSA-N 0.000 description 1
- VNACOBVZDCLAEV-UHFFFAOYSA-N 6-[2-[[2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl]amino]ethylamino]pyridine-3-carbonitrile;dihydrochloride Chemical compound Cl.Cl.C1CCC(C#N)N1C(=O)CNCCNC1=CC=C(C#N)C=N1 VNACOBVZDCLAEV-UHFFFAOYSA-N 0.000 description 1
- VFFZWMWTUSXDCB-ZDUSSCGKSA-N 6-[2-[[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]ethylamino]pyridine-3-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNCCNC1=CC=C(C#N)C=N1 VFFZWMWTUSXDCB-ZDUSSCGKSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- 101710129138 ATP synthase subunit 9, mitochondrial Proteins 0.000 description 1
- 101710168506 ATP synthase subunit C, plastid Proteins 0.000 description 1
- 101710114069 ATP synthase subunit c Proteins 0.000 description 1
- 101710197943 ATP synthase subunit c, chloroplastic Proteins 0.000 description 1
- 101710187091 ATP synthase subunit c, sodium ion specific Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229940104915 Alpha 2 adrenoreceptor antagonist Drugs 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
- 244000144730 Amygdalus persica Species 0.000 description 1
- 101710145634 Antigen 1 Proteins 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- CCDOJMRXXXXXHT-UHFFFAOYSA-N CC(C)(C)C.N Chemical class CC(C)(C)C.N CCDOJMRXXXXXHT-UHFFFAOYSA-N 0.000 description 1
- BYTJFDVPZULBPF-UHFFFAOYSA-N CC(C)(C)C=C.N Chemical class CC(C)(C)C=C.N BYTJFDVPZULBPF-UHFFFAOYSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- DDYJDIHOSRTMSE-FLIBITNWSA-N CGP 52608 Chemical compound CNC(=S)N\N=C1/SCC(=O)N1CC=C DDYJDIHOSRTMSE-FLIBITNWSA-N 0.000 description 1
- PHKYGBHARUTZOY-UHFFFAOYSA-N CKD-711 Natural products OC1C(O)C(NC2C(C(O)C(O)C3(CO)OC32)O)C(CO)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O PHKYGBHARUTZOY-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- WQOXQRCZOLPYPM-UHFFFAOYSA-N Dimethyl disulfide Natural products CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 101710118908 Fatty acid-binding protein, adipocyte Proteins 0.000 description 1
- 102100023374 Forkhead box protein M1 Human genes 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Chemical class NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000007390 Glycogen Phosphorylase Human genes 0.000 description 1
- 108010046163 Glycogen Phosphorylase Proteins 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000907578 Homo sapiens Forkhead box protein M1 Proteins 0.000 description 1
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 1
- 101000716695 Homo sapiens Solute carrier family 5 member 4 Proteins 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 108010084048 Human Isophane Insulin Proteins 0.000 description 1
- 102000005561 Human Isophane Insulin Human genes 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ULXYQAJWJGLCNR-YUMQZZPRSA-N Leu-Asp-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O ULXYQAJWJGLCNR-YUMQZZPRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101150060255 MZB1 gene Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027525 Microalbuminuria Diseases 0.000 description 1
- 102100040216 Mitochondrial uncoupling protein 3 Human genes 0.000 description 1
- 101710112412 Mitochondrial uncoupling protein 3 Proteins 0.000 description 1
- 101100462550 Mus musculus Adcyap1 gene Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 208000016222 Pancreatic disease Diseases 0.000 description 1
- 102000052651 Pancreatic hormone Human genes 0.000 description 1
- 108700020479 Pancreatic hormone Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- NEZJDVYDSZTRFS-RMPHRYRLSA-N Phenyl beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1 NEZJDVYDSZTRFS-RMPHRYRLSA-N 0.000 description 1
- 229940126902 Phlorizin Drugs 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 description 1
- 108010005991 Pork Regular Insulin Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 235000004789 Rosa xanthina Nutrition 0.000 description 1
- 241000220222 Rosaceae Species 0.000 description 1
- 108091006296 SLC2A1 Proteins 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100020883 Solute carrier family 5 member 4 Human genes 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- ODKDMMTXTVCCLJ-UHFFFAOYSA-N TMC-2A Natural products C1=CC=C2C(CC(N)C(=O)N3C(CC4=CC(O)=C(C(=C4C3)O)OC)C(=O)NC(CC(CO)CO)C(O)=O)=CNC2=C1 ODKDMMTXTVCCLJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical class CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 201000010390 abdominal obesity-metabolic syndrome 1 Diseases 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
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940062328 actos Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N alpha-naphthoic acid Natural products C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940000806 amaryl Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229940062310 avandia Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960002536 benzathine benzylpenicillin Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- BVGLIYRKPOITBQ-ANPZCEIESA-N benzylpenicillin benzathine Chemical compound C=1C=CC=CC=1C[NH2+]CC[NH2+]CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 BVGLIYRKPOITBQ-ANPZCEIESA-N 0.000 description 1
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 241000902900 cellular organisms Species 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000000080 chela (arthropods) Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 230000003098 cholesteric effect Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940046374 chromium picolinate Drugs 0.000 description 1
- GJYSUGXFENSLOO-UHFFFAOYSA-N chromium;pyridine-2-carboxylic acid Chemical compound [Cr].OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1 GJYSUGXFENSLOO-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- PHKYGBHARUTZOY-KTVVNDHVSA-N ckd-711 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@]2(CO)O[C@@H]21)O)CO)[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O PHKYGBHARUTZOY-KTVVNDHVSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 125000004979 cyclopentylene group Chemical group 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical class C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013118 diabetic mouse model Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical compound C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 description 1
- PXLWOFBAEVGBOA-UHFFFAOYSA-N dihydrochalcone Natural products OC1C(O)C(O)C(CO)OC1C1=C(O)C=CC(C(=O)CC(O)C=2C=CC(O)=CC=2)=C1O PXLWOFBAEVGBOA-UHFFFAOYSA-N 0.000 description 1
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229950000269 emiglitate Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 230000001610 euglycemic effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 229950003707 farglitazar Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 108010084802 galparan Proteins 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- BOVGTQGAOIONJV-UHFFFAOYSA-N gliclazide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CC2CCCC2C1 BOVGTQGAOIONJV-UHFFFAOYSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- 239000003850 glucocorticoid receptor antagonist Substances 0.000 description 1
- 229940095884 glucophage Drugs 0.000 description 1
- 125000005640 glucopyranosyl group Chemical group 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 108010070004 glucose receptor Proteins 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229940088991 glucotrol Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229940084937 glyset Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 229960004717 insulin aspart Drugs 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
- 230000006362 insulin response pathway Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- GSXOAOHZAIYLCY-HSUXUTPPSA-N keto-D-fructose 6-phosphate Chemical compound OCC(=O)[C@@H](O)[C@H](O)[C@H](O)COP(O)(O)=O GSXOAOHZAIYLCY-HSUXUTPPSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- 102000019758 lipid binding proteins Human genes 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229950007687 macrogol ester Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000011661 metabolic syndrome X Diseases 0.000 description 1
- 229940035734 metformin and sulfonylureas Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- IVAQJHSXBVHUQT-ZVHZXABRSA-N methyl (e)-3-(3,5-dimethoxyphenyl)-2-[4-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]phenyl]prop-2-enoate Chemical compound C=1C=C(OC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)C=CC=1/C(C(=O)OC)=C\C1=CC(OC)=CC(OC)=C1 IVAQJHSXBVHUQT-ZVHZXABRSA-N 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229950001628 netoglitazone Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 229940112879 novolog Drugs 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
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 208000024691 pancreas disease Diseases 0.000 description 1
- 239000004025 pancreas hormone Substances 0.000 description 1
- 229940032957 pancreatic hormone Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- RLLPVAHGXHCWKJ-UHFFFAOYSA-N permethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 RLLPVAHGXHCWKJ-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- FCJSHPDYVMKCHI-UHFFFAOYSA-N phenyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1=CC=CC=C1 FCJSHPDYVMKCHI-UHFFFAOYSA-N 0.000 description 1
- 125000006187 phenyl benzyl group Chemical group 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000008106 phosphatidylserines Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- HRNLPPBUBKMZMT-RDRUQFPZSA-N pralmorelin Chemical compound C([C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](C)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)[C@H](N)C)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 HRNLPPBUBKMZMT-RDRUQFPZSA-N 0.000 description 1
- 229940096058 prandin Drugs 0.000 description 1
- 229940095885 precose Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N pyrocatechol monomethyl ether Natural products COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229950006433 risarestat Drugs 0.000 description 1
- 229960003271 rosiglitazone maleate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940043230 sarcosine Drugs 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
- 238000010956 selective crystallization Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940110862 starlix Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940099093 symlin Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- ODKDMMTXTVCCLJ-BVSLBCMMSA-N tmc-2-a Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N3[C@@H](CC4=CC(O)=C(C(=C4C3)O)OC)C(=O)N[C@@H](CC(CO)CO)C(O)=O)=CNC2=C1 ODKDMMTXTVCCLJ-BVSLBCMMSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229940035266 tolinase Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940110253 toujeo Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QENJZWZWAWWESF-UHFFFAOYSA-N tri-methylbenzoic acid Natural products CC1=CC(C)=C(C(O)=O)C=C1C QENJZWZWAWWESF-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940055755 tricor Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- UUUGYDOQQLOJQA-UHFFFAOYSA-L vanadyl sulfate Chemical compound [V+2]=O.[O-]S([O-])(=O)=O UUUGYDOQQLOJQA-UHFFFAOYSA-L 0.000 description 1
- 229940041260 vanadyl sulfate Drugs 0.000 description 1
- 229910000352 vanadyl sulfate Inorganic materials 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 1
- 229930195724 β-lactose Natural products 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
- A61K31/425—Thiazoles
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
-
- 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
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/4196—1,2,4-Triazoles
-
- 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
- A61K31/41—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
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- 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
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
本发明公开了用于治疗糖尿病和X综合征的含有RXR调节剂和葡萄糖重吸收直接的联合疗法。
Description
交叉参考相关申请
本申请请求以2001年4月4日提交的临时申请U.S.S.N60/281,479(我们的登记号为ORT-1410)为优先权,该申请在此引入作为参考。
发明领域
本发明涉及治疗或预防糖尿病和X综合征(Syndrome X)的新方法和组合物。
发明背景
糖尿病是动物中一种影响碳水化合物、脂肪和蛋白质代谢的慢性疾病。
I型糖尿病,它占总糖尿病病例的约10%,早先被称作胰岛素依赖性糖尿病(“IDDM”)或幼年发作糖尿病。这种糖尿病的特征在于胰腺的β细胞的胰岛素分泌功能的进行性丧失。这种特征也表现在非自发性,或“继发性”具有胰腺疾病来源的糖尿病。I型糖尿病与下列临床症候或症状有关:血浆葡萄糖浓度持续升高或高血糖症;多尿;烦渴和/或食欲过盛;和大血管并发症,例如高脂血症和高血压,其可导致失明、晚期肾病、断肢和心肌梗塞。
II型糖尿病(非胰岛素依赖性糖尿病或NIDDM)是一种涉及葡萄糖代谢的调节异常和受损胰岛素敏感性的代谢性疾病。II型糖尿病通常在成年阶段恶化并与机体无能力利用或制造足够的胰岛素有关。除了在靶向组织中观察到胰岛素耐受性以外,患有II型糖尿病的患者具有相对的胰岛素缺失-也就是说,患者对于指定血浆葡萄糖浓度具有低于预定的胰岛素水平。II型糖尿病的特征在于下列临床症候或症状:持续血浆葡萄糖浓度升高或高血糖;多尿;烦渴和/或食欲过盛;慢性微血管并发症例如视网膜病、肾病和神经病;和大血管并发症例如高脂血症和高血压,其可导致失明、晚期肾病、断肢和心肌梗塞。
X综合征,也称作抗胰岛素综合征(IRS)、代谢性综合征,或代谢性综合征X,在诊断性冠状插管术中被发现约有2%,经常不幸的,它存在使II型糖尿病和心血管疾病的恶化的症状或危险因素,包括损坏的葡萄糖耐受性(IGT)、损坏的禁食葡萄糖(IFG)、高胰岛素血症、胰岛素耐受性、异常脂血症(例如高甘油三酯、低HDL)、高血压和肥胖。
对于IDDM患者的治疗始终着重于施用外源性胰岛素,其可以衍生自多种来源(例如人、牛、猪胰岛素)。异种物质的使用导致抗胰岛素抗体的形成,其具有活性有限的在于并导致逐步需要大剂量以获得预期的降血糖效果。
II型糖尿病的典型治疗着重于通过涉及饮食和锻练的生活方式改变尽可能地使血糖水平维持在接近于正常水平,并且在需要时,用糖尿病治疗药、胰岛素或其联合形式治疗。无法通过饮食管理控制住的NIDDM是用口服糖尿病治疗药治疗。
尽管在所有X综合征患者中不总是治疗胰岛素耐受性,但表现出糖尿病前期状态(例如IGT、IFG)的患者,其禁食的葡萄糖水平可以高于正常水平但不属于糖尿病诊断标准范畴内,在一些国家(例如德国)是用二甲双胍处理以预防糖尿病。糖尿病治疗药可以与治疗并发病的药物(例如治疗高血压的高血压药物,治疗脂血症的降血症药物)联合使用。
一线治疗剂通常包括二甲双胍和磺酰脲类以及噻唑烷二酮类。二甲双胍单独疗法是一线首选,特别是治疗还肥胖和/或异常脂血症的II型糖尿病患者。对于二甲双胍缺乏适当反应常常随后用二甲双胍与磺酰脲列、噻唑烷二酮类或胰岛素联合治疗。磺酰脲单独疗法(包括所有代的药物)常常也是一线首选。另一一线首选治疗剂可以是噻唑烷二酮类。α葡糖苷酶抑制剂也用作一线和二线的治疗剂。对口服抗糖尿病单独疗法没有适当反应的患者,给予上述药物的联合形式。当用单独口服抗糖尿病药物无法维持血糖控制时,或者单独采用胰岛素疗法,或者与口服糖尿病治疗剂联合。
高血糖治疗中一种最新研发着重于将过量葡萄糖直接排泄到尿内。在IDDM和NIDDM的啮齿动物模型中已经证实SGLT类的特定抑制剂增强葡萄糖排泄到尿中并降低葡萄糖水平。然而,包括维生素A类-X受体(RXR)调节剂和葡萄糖重吸收抑制剂的联合治疗迄今不曾在现有技术中公开。
发明概述
本发明涉及用于治疗或预防糖尿病、X综合征,或有关症状或并发症的方法和组合物。更具体地,本发明涉及在患有所述病症的对象中治疗糖尿病或X综合征,或其有关症状或并发症的新方法,该方法包括施用一种或多种葡萄糖重吸收抑制剂并施用一种或多种RXR调节剂从而治疗糖尿病或X综合征,或其相关症状或并发症。
本发明的一个方面特征在于一种含有葡萄糖重吸收抑制剂、RXR调节剂和药学可接受载体的药物组合物。本发明还提供一种配制该药物组合物的方法,包括将葡萄糖重吸收抑制剂、RXR调节剂和药学可接受载体一起配制。
本发明的一个实施方式是一种治疗对象中的糖尿病或X综合征,或其有关症状或并发症的方法,该方法包括给该对象施用合用有效量的葡萄糖重吸收抑制剂并给该对象施用合用有效量的RXR调节剂,该联合给药产生预期的治疗效果。
本发明的另一实施方式是一种抑制糖尿病或X综合征,或其症状或并发症的发作的方法,该方法包括给该对象施用合用有效量的葡萄糖重吸收抑制剂并给该对象施用合用有效量的RXR调节剂,该联合给药产生预期的预防效果。
在所公开的方法中,糖尿病或X综合征,或其有关症状或并发症,选自IDDM、NIDDM、IGT IFG、肥胖、肾病、神经病、视网膜病、动脉粥样硬化、多囊性卵巢综合征或多囊性卵巢性综合征、高血压、局部缺血、中风、心脏病、刺激性肠病、炎症和白内障。
本发明还涉及一种或多种葡萄糖重吸收抑制剂与一种或多种RXR调节剂在制备用于治疗选自下列病症的药物中的用途:IDDM、NIDDM、IGT、IFG、肥胖、肾病、神经病、视网膜病、动脉粥样硬化、多囊性卵巢综合征或多囊性卵巢性综合征、高血压、局部缺血、中风、心脏病、刺激性肠病、炎症和白内障。
发明详述
所有糖尿病患者,无论其遗传和环境背景,普遍明显缺乏胰岛素或胰岛素功能不足。由于葡萄糖从血液向肌肉和脂肪组织内的转移是胰岛素依赖性的,所以糖尿病患者没有能力充分利用葡萄糖,这导致所不期望的葡萄糖在血液中的蓄积(高血糖症)。慢性高血糖症使胰岛素分泌减少并造成胰岛素耐受性增高,由此,血糖浓度升高,糖尿病是自身恶化(Diabetologia,1985,“高血糖是损伤胰岛细胞功能和胰岛素抗性的诱导因素及后果:糖尿病控制的启示”,Vol.28,p.119);DiabetesCares,1990,Vol.13,No.6,“葡萄糖毒性”,pp.610-630)。所以,通过治疗高血糖,上述自身恶化循环被打断,从而可能预防或治疗糖尿病。
R.Rieveley的美国专利No.6,153,632公开了一种据称用于治疗糖尿病(I型,受损的葡萄糖耐受性[“IGT”]和II型)的方法和组合物,其结合治疗量的一种或多种胰岛素致敏物与一种或多种口服胰岛素、注射胰岛素、磺酰脲、双胍或α-葡糖苷酶抑制剂来治疗糖尿病。
根据一个方面,本发明特征在于PPAR调节剂,优选PPARδ激动剂和SGLT抑制剂,优选SGLT2抑制剂或选择性SGLT2抑制剂的联合形式。
A.术语
一些术语定义如下且在本内容中通用。
除非另外说明,在此使用的“烷基”和“烷氧基”,无论是单独使用或是作为取代基的组成部分,包括直链、环状和支链的具有1-8个碳原子、或此范围内任意数目碳原子的烷基。例如,烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、2-丁烯基、2-丁炔基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基和2-甲基戊基。烷氧基是由上述直链或支链烷基形成的氧醚类。烷基和烷氧基可独立地被1-5个、优选1-3个选自卤素(F、Cl、Br、I)、氧代、OH、胺、羧基和烷氧基的基团取代。烷基和烷氧基还可以独立地与一个或多个PEG基团(聚乙二醇)相连。
在此使用的术语“酰基”,无论单独使用或作为取代基的组成部分,是指具有2-6个碳原子(支链或直链)的由有机酸通过脱去羟基衍生的有机基团。酰基是,例如,选择性取代的C2-C20烷酰基、低级烷氧基-低级烷酰基、选择性取代的低级烷氧基羰基、选择性取代的苯甲酰基、选择性取代的苯氧基羰基,或由相应氨基酸(其中氨基和/或羧基在该残基中可以用常规保护基保护)的羧基通过脱羟基得到的氨基酸残基。在此使用的术语“Ac”,无论单独使用或作为取代基的组成部分,是指乙酰基。
“芳基”是指碳环芳基,包括不限于,苯基、1-或2-萘基等。碳环芳基其上的1-3氢原子可以独立地被卤素、OH、CN、巯基、硝基、氨基、氰基、选择性取代的C1-C8-烷基、选择性取代的烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基-氨基、二(C1-C8-烷基)氨基、甲酰基、羧基、烷氧基羰基、烷氧基羰氧基、烷酰氧基、苯基、氨基甲酰基、甲酰胺基、二-低级烷基氨基甲酰基氧基、苯氧基羰氧基、亚烷基二氧基、苯甲酰氧基、烷基-CO-O-、烷基-O-CO-、-CONH2、烷基-O-CO-O-或烷基-CO-NH-。示例芳基包括,例如,苯基、萘基、联苯基、茚二氢茚氟苯基、二氟苯基、苄基、苯甲酰氧基苯基、羧乙氧基苯基、乙酰基苯基、乙氧基苯基、苯氧基苯基、氰基苯基、羧基苯基、三氟甲基苯基、甲氧基乙基苯基、乙酰氨基苯基、甲苯基、二甲苯基、二甲基氨基甲酰基苯基等。“Ph”或“PH”代表苯基。
在此使用的术语“杂芳基”代表稳定的5或6员单环或双环芳环体系,其由碳原子和1-3个选自N、O和S的杂原子组成。该杂芳基可以在任何杂原子或碳原子上连接,得到稳定结构。杂芳基的实例包括,但不限于苯并呋喃基、苯并噻吩基、吡啶基、吡嗪基、哒嗪基、嘧啶基、噻吩基、呋喃基、咪唑基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异噁唑基、苯并噁唑基、苯并吡唑基、吲哚基、苯并三唑基、苯并噻二唑基、苯并三唑基或喹啉基。优选的杂芳基包括吡啶基、噻吩基、呋喃基和喹啉基。当杂芳基被取代时,该杂芳基可以具有1-3个取代基,该取代基独立地选自卤素、OH、CN、巯基、硝基、氨基、氰基、选择性取代的C1-C8-烷基、选择性取代的烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基-氨基、二(C1-C8-烷基)氨基、甲酰基、羧基、烷氧基羰基、烷氧基羰氧基、烷酰氧基、苯基、氨基甲酰基、甲酰胺基、二-低级烷基氨基甲酰基氧基、苯氧基羰氧基、亚烷基二氧基、苯甲酰氧基、烷基-CO-O-、烷基-O-CO-、-CONH2、烷基-O-CO-O-或烷基-CO-NH-。
在此使用的术语“杂环”、“杂环的”和“杂环基”是指选择性取代的、完全或部分饱和的环状基团,它例如是4-至7-员单环,7-至11-员双环,或10-至15-员三环环系,其在至少一个含于环内的碳原子上具有至少一个杂原子。含有杂原子的杂环基的各个环可以具有1、2或3个选自氮原子、氧原子和硫原子的杂原子,其中氮和硫杂原子业可以被选择性地氧化。氮原子可以选择性地季铵化。杂环基可以在任何杂原子或碳原子上连接。
示例单环杂环基包括吡咯烷基;氧杂环丁烷基;吡唑啉基;咪唑啉基;咪唑烷基;噁唑基;噁唑烷基;异噁唑啉基;噻唑烷基;异噻唑烷基;四氢呋喃基;哌啶基;哌嗪基;2-氧代哌嗪基;2-氧代哌啶基;2-氧代吡咯烷基;4-哌啶酮基;四氢吡喃基;四氢硫代吡喃基;四氢硫代吡喃基砜;吗啉基;硫代吗啉基;硫代吗啉基亚砜;硫代吗啉基砜;1,3-二氧杂环戊烷;二噁烷基;硫杂环丁烷基;硫杂环丙烷基;等等。示例双环杂环基包括奎宁啶基;四氢异喹啉基;二氢异吲哚基;二氢喹啉基(例如3,4-二氢-4-氧代-喹唑啉基);二氢苯并呋喃基;二氢苯并噻吩基;二氢苯并硫代吡喃基;二氢苯并硫代吡喃基砜;二氢苯并吡喃基;吲哚啉基;异色满基;异吲哚啉基;胡椒基;四氢喹啉基;等等。当该杂芳基被取代时,杂环基可以独立地被1-5个、优选1-3个选自卤素、OH、CN、巯基、硝基、氨基、氰基、选择性取代的C1-C8-烷基、选择性取代的烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基-氨基、二(C1-C8-烷基)氨基、甲酰基、羧基、烷氧基羰基、烷氧基羰氧基、烷酰氧基、苯基、氨基甲酰基、甲酰胺基、二-低级烷基氨基甲酰基氧基、苯氧基羰氧基、亚烷基二氧基、苯甲酰氧基、烷基-CO-O-、烷基-O-CO-、-CONH2、烷基-O-CO-O-或烷基-CO-NH-的取代基取代。
术语“组合物”包括含有所述量的所述组分的产品,以及任何直接或间接由所述量的所述组分的联合得到的产品。
术语“联合给药”包括合并给药,其中:1)两种或多种药物基本上在同一时间施用给对象;和2)两种或多种药物在不同的时间、以独立的时间间隔施用给对象,所述时间间隔可以或可以不重叠或一致。
在此使用的术语“对象”是指动物,优选哺乳动物,首选人,其是治疗、观察或试验的主体。
在此使用的术语“RXR调节剂”是指维生素A类-X受体激动剂、部分激动剂或拮抗剂。优选该调节剂提高胰岛素敏感性。按照一个方面,该调节剂是RXR激动剂。
糖尿病,X综合征,或其有关症状或并发症包括例如IDDM、NIDDM、IGT、IFG、肥胖、肾病、神经病、视网膜病、动脉粥样硬化、多囊性卵巢综合征或多囊性卵巢性综合征、高血压、局部缺血、中风、心脏病、刺激性肠病、炎症和白内障的病症。
所属领域了解出于治疗和预防目的来测定所述药物组合物或所述药物联合形式的有效量的方法,而无论是否配制成相同的组合物。对于治疗目的,在此使用的术语“合用有效量”是指各活性化合物和药物,单独或联合地,在组织系统、动物或人中产生能够被研究者、兽医、医生或其他临床工作人员寻找到的生物或医学反应时的量,其包括减轻被治疗疾病或障碍的症状。对于预防目的(即,抑制疾病的发作或发展),术语“合用有效量”是指各活性化合物或药物,单独或联合地,抑制对象中疾病的发作或发展的可以被研究者、兽医、医生或其他临床工作人员寻找到的量,所述疾病的延迟是通过调节葡萄糖重吸收活性或RXR活性或两者来介导的。所以,本发明提供两种或多种药物的联合形式,例如(a)各药物以独立治疗或预防的有效量给药;(b)至少一种联合药物是以如果单独给药是亚治疗或亚预防性、而当与本发明的第二附加药物联合给药时却是治疗或预防性的量给药;或(c)两种药物是以如果单独给药为亚治疗或亚预防性、而当共同给药时却是治疗或预防性的量给药。
术语“保护基”是指那些所属领域技术人员已知的用来掩蔽官能团的部分;保护基可以在后续合成转化过程中脱除或通过代谢或其他体内给药条件下脱除。在本发明化合物的任何制备方法中,可能需要和/或希望保护位于任何所关心分子上的敏感或反应性基团。这可以利用常规保护基的方式来达到,例如,如Protective Groups in OrganicChemisry,ed.J.F.W.Mcomle.Plenum Press,1973;和T.W.Greene &P.G.M.Wuts.Protective Groups in Organic Synthesis,Third Edition,John Wiley & Sons,1999.所述的那些。保护基可以在常规后续阶段利用所属领域的已知方法脱除。下面提供羟基和二醇保护基的实例。
羟基保护包括甲基醚类、取代的甲基醚类、取代的乙基醚类、取代的苄基醚类,和甲硅烷基醚类。
取代的甲基醚类
取代的甲基醚类的实例包括甲氧基甲基、甲硫基甲基、叔丁硫基甲基、(苯基二甲基甲硅烷基)甲基甲基、苄氧基甲基、对甲氧基苄氧基甲基、(4-甲氧基苯氧基)甲基、愈创木酚甲基、叔丁氧基甲基、4-戊烯氧基甲基、甲硅烷氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯乙氧基甲基、二(2-氯乙氧基)甲基、2-(三甲基甲硅烷基)乙氧基甲基、四氢吡喃基、3-溴四氢吡喃基、四氢硫代吡喃基、1-甲氧基环己基、4-甲氧基四氢吡喃基、4-甲氧基四氢硫代吡喃基、4-甲氧基四氢硫代吡喃基S,S-二桥氧基(dioxido)、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基、1,4-二噁烷-2-基、四氢呋喃基、四氢硫代呋喃基和2,3,3a,4,5,6,7,7a-八氢-7,8,8-三甲基-4,7-甲烷苯并呋喃-2-基。
取代的乙基醚类
取代的乙基醚类的实例包括1-乙氧基乙基、1-(2-氯乙氧基)乙基、1-甲基-1-甲氧基乙基、1-甲基-1-苄氧基乙基、1-甲基-1-苄氧基-2-氟乙基、2,2,2-三氯乙基、2-三甲基甲硅烷基乙基、2-(苯基氢硒基)乙基、叔丁基、烯丙基、对氯苯基、对甲氧基苯基、2,4-二硝基苯基、苄基,和聚乙二醇醚。
取代的苄基醚类
取代的苄基醚类的实例包括对甲氧基苄基、3,4-二甲氧基苄基、邻硝基苄基、对硝基苄基、对卤代苄基、2,6-二氯苄基、对氰基苄基、对苯基苄基、2-和4-吡啶甲基、3-甲基-2-吡啶甲基N-氧桥、二苯基甲基、p,p’-二硝基二苯甲基、5-二苯并suberyl、三苯基甲基、α-萘基二苯基甲基、对甲氧基苯基二苯基甲基、二(对-甲氧基苯基)苯基甲基、三(对甲氧基苯基)甲基、4-(4’-溴苯甲酰氧基)苯基二苯基甲基、4,4’,4”-三(4,5-二氯苯二甲酰亚氨基苯基)甲基、4,4’,4”-三(乙酰丙酰氧基苯基)甲基、4,4’,4”-三(苯甲酰氧基苯基)甲基、3-(咪唑-1-基甲基)二(4’,4”-二甲氧基苯基)甲基、1,1-二(4-甲氧基苯基)-1’-苯基甲基、9-蒽基、9-(9-苯基)占吨基、9-(9-苯基-10-氧代)蒽基、1,3-苯并二硫戊环-2-基,和苯并异噻唑基S,S-二氧桥。
甲硅烷基醚类
甲硅烷基醚的实例包括三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二甲基异丙基甲硅烷基、二乙基异丙基甲硅烷基、二甲基(三甲基丙基)甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、三苄基甲硅烷基、三对(二苯基)甲硅烷基、三苯基甲硅烷基、二苯基甲基甲硅烷基,和叔丁基甲氧基苯基甲硅烷基。
酯
除了醚以外,羟基可以保护为酯。酯的实例包括甲酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、对氯苯氧基乙酸酯、对P苯基乙酸酯、3-苯基丙酸酯、4-氧代戊酸酯(乙酰丙酸酯)、4,4-(亚乙基二硫代)戊酸酯、新戊酸酯、金刚烷酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、对苯基苯甲酸酯、2,4,6-三甲基苯甲酸酯(三甲基苯甲酸酯),和聚乙二醇酯。
碳酸酯
碳酸酯的实例包括甲基、9-芴基甲基、乙基、2,2,2-三氯乙基、2-(三甲基甲硅烷基)乙基、2-(苯基磺酰基)乙基、2-(三苯基磷翁基)乙基、异丁基、乙酰基、烯丙基、对硝基苯基、苄基、对甲氧基苄基、3,4-二甲氧基苄基、邻硝基苄基、对硝基苄基、S-苄基硫代碳酸酯、4-亚乙基-1-萘基、甲基二硫代调整,和聚乙二醇碳酸酯。
辅助断裂
辅助断裂的实例包括2-碘苯甲酸酯、4-叠氮基丁酸酯、4-硝基-4-甲基戊酸酯、邻-(二溴甲基)苯甲酸酯、2-甲酰基苯磺酸酯、2-(甲硫基甲氧基)乙基碳酸酯、4-(甲硫基甲氧基)丁酸酯,和2-(甲硫基甲基甲基)苯甲酸酯。
杂酯
杂酯的实例包括2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-二(1,1-二甲基丙基)苯氧基乙酸酯、氯二苯基乙酸酯、异丁酸酯、琥珀酸一酯、(E)-2-甲基-2-丁烯酸酯(惕各酸酯)、邻-(甲氧基羰基)苯甲酸酯、对P苯甲酸酯、α-萘酸酯、硝酸酯、烷基N,N,N’,N’-四甲基磷二酰胺酯、N-苯基氨基甲酸酯、硼酸酯、二甲基硫膦基,和2,4-二硝基苯基次磺酰基。
磺酸酯
磺酸酯的实例包括硫酸酯、甲磺酸酯、苄基磺酸酯,和甲苯基磺酸酯。
对1,2-和1,3-二醇的保护
环状缩醛和缩酮
环状缩醛和缩酮的实例包括有机碱、亚乙基、1-叔丁基亚乙基、1-苯基亚苯基、(4-甲氧基苯基)亚乙基、2,2,2-三氯亚乙基、丙酮化合物(亚异丙基)、亚环戊基、亚环己基、亚环庚基、亚苄基、对甲氧基亚苄基、2,4-二甲氧基亚苄基、3,4-二甲氧基亚苄基,和2-硝基亚苄基。
环状原酸酯
环状原酸酯的实例包括甲氧基亚甲基、乙氧基亚甲基、二甲氧基亚甲基、1-甲氧基亚乙基、1-乙氧基次乙基、1,2-二甲氧基亚乙基、α-甲氧基亚苄基、1-(N,N-二甲基氨基)亚乙基衍生物、α-(N,N-二甲基氨基)亚苄基衍生物,和2-氧杂亚环戊基。
甲硅烷基衍生物
甲硅烷基衍生物的实例包括二叔丁基亚甲硅烷基,和1,3-(1,1,3,3-四异丙基二亚硅氧烷基)衍生物。
B.葡萄糖重吸收抑制剂
治疗高血糖的一种方法是将过量的葡萄糖直接排泄到尿中使血糖浓度正常化。譬如,主要在肠和肾的绒毛膜内发现的钠-葡萄糖协调转运蛋白(SGLT),是一个家族的在葡萄糖吸收正常过程中具有活性的蛋白。其中,SGLT1存在于肠和肾上皮细胞内(Lee等,1994),其中在肾脏的上皮中发现SGLT2(You等,1995,MacKenzie等,1994)。肠中的葡萄糖吸收主要是通过SGLT1介导的,它是具有2∶1的Na+∶葡萄糖转运比例的高亲和力转运蛋白。SGLT2,业称作SAAT1,以1∶1的比例转运Na+和葡萄糖且充当低亲和力高容量转运蛋白。这些SGLT类特征如表1所示:
表1
*(mM)是指D-葡萄糖
**最大转运速率pmol/分钟/mm
葡萄糖的肾脏吸收是通过SGLT1和SGLT2介导的(Silverman等,1992;Deejen等,1995)。血浆葡萄糖在肾小球内过滤并在近端小管内跨上皮重吸收。SGLT1和SGLT2位于上皮的顶血浆膜且其能力源自位于基底外侧模上的Na+/K ATP酶泵提供的内流钠梯度。一旦被重吸收,升高的胞质葡萄糖随后被易化的葡萄糖转运(GLUT1和GLUT)转运到胞间隙内。所以,SGLT类的抑制通过抑制肾脏的葡萄糖重吸收减少了血浆葡萄糖。利用所属领域已有的方法可以很容易地测定出SGLT抑制剂的治疗或预防有效量,例如足以提供尿葡萄糖排泄,或减少对象中每天的血浆葡萄糖的所需量。目前,已经发现,根皮甙(phlorizin),一种存在于Rosaceae(例如苹果、桃等)的树皮和干中的天然糖甙,抑制位于肠和肾的绒毛膜中的Na+-葡萄糖协调转运蛋白。通过抑制Na+-葡萄糖协调转运蛋白的活性,根皮甙抑制肾小管葡萄糖重吸收并促进葡萄糖的排泄,使经过每天皮下给药长时间将血浆中的葡萄糖水平控制在正常水平(Journal of Clinical Investigation,1987,vol.79,p 1510)。
JP 8-347406(提交于1996年12月26日)和美国专利Nos.5767094、5830873和6048842(全部属于Tanabe Seiyaku Co.,Ltd.)公开了通过抑制钠-葡萄糖协调转运蛋白活性具有降血糖活性的苯基·乙基(甲)酮衍生物。JP2762903、JP2795162、JP2906978和美国专利Nos.5424406和5731292(全部属于Tanabe Seiyaku Co.,Ltd.)公开了基于其尿葡萄糖增强作用的降血糖活性的二氢查耳酮衍生物。
特别是,美国专利NO 6048842公开了有效治疗和/或预防糖尿病的化合物或其药学可接受盐,其具有式I的结构:
其中OX是可以被选择性保护的羟基,Y是低级烷基,和Z是其中一个或多个羟基可以被选择性地保护的β-D-吡喃葡萄糖基,。
当式I的OX是被保护的羟基时,保护基可以是任何保护基,其可以是用于保护酚羟基的保护基,例如,低级烷氧基-低级烷基例如甲氧基甲基;烯丙基;和酰基,例如低级烷酰基,低级烷氧基-低级烷酰基,低级烷氧基羰基,低级烷氧基-低级烷氧基羰基,芳基羰基(例如苯甲酰基)。在这些保护基中,有效酰基例如低级烷酰基、低级烷氧基-低级烷酰基、低级烷氧基羰基、低级烷氧基-低级烷氧基羰基,并且尤其有效低级烷酰基,和低级烷氧基羰基。
当式I的Z是其中一个或多个羟基被保护的β-D-吡喃葡萄糖基时,保护基可以是任何常规的羟基保护基,其通过常规方法例如酸处理、水解、还原等很容易除去。其中一个或多个羟基被上述保护基保护的β-D-吡喃葡萄糖基可以选自(i)其中一个或多个羟基被酰化的β-D-吡喃葡萄糖基,(ii)其中两个羟基结合与其保护基一起形成1-低级烷氧基-低级亚烷基二氧基、亚苄基二氧基、磷翁基二氧基或羰基二氧基的β-D-吡喃葡萄糖基;和(iii)其中一个或两个羟基被酰化,并且其他两个羟基与其保护基一起形成1-低级烷氧基-低级亚烷基二氧基、亚苄基二氧基、磷翁基二氧基或羰基二氧基的β-D-吡喃葡萄糖基。然而,β-D-吡喃葡萄糖基的羟基保护基应不限于上述保护基,并且可以是任何可以在施用本发明化合物到生命体内后脱除并释放出β-D-吡喃葡萄糖基的羟基,或者可以促进所需化合物吸收到生命体内的保护基,或者使本发明的化合物更容易施用到生命体内,或者可以提供本发明在油和/或水中的溶解度的保护基。
当β-D-吡喃葡萄糖基被酰化时,酰基优选是低级烷酰基、低级烷氧基-低级烷酰基、低级烷氧基羰基、低级烷氧基-低级烷氧基羰基,或芳基羰基(例如苯甲酰基),或通过除去相应氨基酸的羧基上的羟基得到的氨基酸残基(其中残基中的氨基和/或羧基和/或羟基可以被常规保护基保护)。氨基残基包括通过除去天然氨基酸如天冬氨酸、谷氨酸、谷氨酰胺、丝氨酸、肌氨酸、脯氨酸、苯病氨酸、亮氨酸、异亮氨酸、甘氨酸、色氨酸、胱氨酸、组氨酸、酪氨酸、缬氨酸,或其对映体,或其外消旋化合物。
当Z是其中β-D-吡喃葡萄糖基的两个羟基与其保护基一起构成1-低级烷氧基-低级亚烷基二氧基、亚苄基二氧基、磷翁基二氧基或羰基二氧基的β-D-吡喃葡萄糖基时,该β-D-吡喃葡萄糖基可以是其中β-D-吡喃葡萄糖基的4-和6-羟基与其保护基一起构成1-低级烷氧基-低级亚烷基二氧基、亚苄基二氧基、磷翁基二氧基或羰基二氧基的β-D-吡喃葡萄糖基。此类β-D-吡喃葡萄糖基具有下面两式之一。
其中R7和R8之一是氢原子或低级烷基,并且另一个是低级烷氧基,或者R7和R8之一式氢原子,并且另一个是苯基,或者R7和R8联合构成氧代基团。
当β-D-吡喃葡萄糖基的两个羟基结合与其保护基一起形成1-低级烷氧基-低级亚烷基二氧基时,该1-低级烷氧基-低级亚烷基二氧基优选是1-低级烷氧基亚乙基二氧基,并且更优选1-甲氧基亚乙基二氧基或1-亚乙基亚乙基二氧基。
式I的Y优选是具有1-4个碳原子的烷基,更优选甲基或乙基。
式I的苯基·乙基(甲)酮衍生物衍生物或其药学可接受盐包括其分子内盐,或溶剂化物或水合物。
此外,美国专利NO 5830873公开了有效治疗和/或预防糖尿病的化合物或其药学可接受盐,其具有式II的结构:
其中X是氧原子、硫原子或亚甲基,OY是被保护的或未保护的羟基,Z是β-D-吡喃葡萄糖基或4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基其中这些基团的一个或多个羟基可以被选择性地酰化,并且虚线表示存在或不存在双键。
此外,美国专利NO.576094公开了有效治疗和/或预防糖尿病的化合物或其药学可接受盐,其具有式III的结构:
其中R’是低级烷酰基,和R”是氢原子,或R’是氢原子,和R”是低级烷氧基羰基。
另外,美国专利No 424406和5731292公开了有效治疗和/或预防糖尿病的化合物或其药学可接受盐,其具有式IV的结构:
其中Ar是芳基,R1是氢原子或酰基,R2是氢原子、酰基或α-D-吡喃葡萄糖基,或R1和R2可以结合与其保护基一起构成被取代的亚甲基,R3和R4分别为氢原子或酰基,和OR5是被保护的或未保护的羟基或低级烷氧基。
其他SGLT抑制剂包括烷基-和苯基葡糖苷、1,5-异喹啉磺酰基)-2-甲基哌嗪-HCl(间接经蛋白激酶C保护)、对-氯汞苯甲酸酯(PCMB)、N,N’-二环己基碳二亚胺(DCCD)、铜和钙离子,和三价镧系。
式I、II、III、IV和V的化合物可以通过美国专利NO 5424406、5731292、5767094、5830873和6048842所公开的方法制备。
C.RXR调节剂
维生素A类-X受体(RXR)调节剂也是胰岛素敏感性药物,其包括,但不限于:
(1)bexarotene(4-(1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-乙烯基)苯甲酸,称作TARGRETIN、TARGRETYN、TARGREXIN;还称作LGD 1069、LG 100069、LG 1069 LG 69 RO 264455)
(2)9-顺式-视黄酸;
(3)AGN-4326(也称作ALRT-42-4、AGN-4204、ALRT-326、ALRT-324,或LGD 1324);
(4)LGD 1324(ALRT 324);
(5)LG 100754;
(6)LY-510929;
(7)LGD 1268(6-(1,1,4,4,6-五甲基-1,2,3,4-四氢-萘-7-基环丙-1-基)烟酸,称作ALRT 268或LG 100268);
(8)LG 100264;和
(9)被取代的杂环例如式VI的化合物,
其中
n和m独立地是0或1;
R1和R2是1)独立地或一起是氢、烷基、取代的烷基、卤代烷基、链烯基、取代的链烯基、炔基、取代的炔基、烷氧基、取代的烷氧基、羟基、酰基、氨基、一取代的氨基、二取代的氨基、羧基、烷氧羰基、烷基甲酰胺、取代的烷基甲酰胺、二烷基甲酰胺、取代的二烷基甲酰胺或卤代烷氧基;或2)R1和R2与其连接的芳环一起构成环烷基、取代的环烷基、环烯基、可以选择性地含有1或2个选自O、S、NH或N-烷基的杂原子的取代的环烯基残基;
R3和R4独立地或一起是氢、烷基、取代的烷基、卤代烷基、链烯基、取代的链烯基、炔基、取代的炔基、卤素、氰基、硝基、羟基、酰氧基、氨基、一取代的氨基、二取代的氨基、烷基磺酰胺、芳基磺酰胺、烷基脲、芳基脲、烷基氨基甲酸酯、芳基氨基甲酸酯、杂芳基、烷氧基、取代的烷基、卤代烷氧基、硫代烷基、硫代卤代烷氧基;羧基,烷氧羰基、烷基甲酰胺、取代的烷基甲酰胺、二烷基甲酰胺、取代的二烷基甲酰胺;
A是-CR6R7-其中R6和R7独立地或一起是氢、烷基、取代的烷基、烷氧基、取代的烷氧基、卤代烷氧基;或R6和R7一起构成环烷基残基,其可以选择性地含1或2个选自O、S、NH或N-烷基的杂原子;
Ar是式VII、VIII、IX或X:
其中R8、R9和R10独立地或一起是氢、烷基、取代的烷基、卤代烷基、链烯基、取代的链烯基、炔基、取代的炔基、卤素、氰基、硝基、羟基、酰氧基、氨基、一取代的氨基、二取代的氨基、烷基酰胺、烷基磺酰胺、芳基磺酰胺、烷基脲、芳基尿、烷基氨基甲酸酯、芳基氨基甲酸酯、烷氧基、取代的烷氧基、卤代烷氧基、硫代烷基、硫代卤代烷基;羧基、烷氧羰基、烷基甲酰胺、取代的烷基甲酰胺、二烷基甲酰胺、取代的二烷基甲酰胺;
R5是氢、卤素、羟基、烷基或取代的烷基;
---表示一个键存在或不存在;和
W、X、Y和Z独立地或一起是-C(O)-、-C(S)-、-S-、-O-或-NH-残基。
式VI的化合物的一个优选实例是MX-6054,其是2,4-噻唑烷二酮,5-[[3-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)-4-(三氟甲氧基)苯基]亚甲基]-、(5Z)-,也称作3-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-4-三氟甲氧基亚苄基-2,4-噻唑烷二酮,由下式表示:
当n是1时,优选R1和R2与它们相连的芳环一起构成选择性含有1或2个选自O、S、NH或N-烷基的杂原子的取代的环烷基,和R3是烷基或取代的烷基。另外优选,A是-CR6R7其中R6和R7独立地或一起是烷基;或R6和R7一起构成含有1或2个氧原子的环烷基并且更优选1,3-二氧杂环戊烷。还优选,基团是2,4-噻唑烷二酮、2-硫代-4-噻唑烷二酮、异噁唑烷二酮、2,4-咪唑烷二酮或2,4-咪唑烷二酮。
优选地,式VI的化合物选自:
3-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-4-三氟甲氧基亚苄基-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2,4-咪唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2,4-咪唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2-硫代-2,4-咪唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2-硫代-2,4-咪唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2,4-咪唑烷二酮;和
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2,4-咪唑烷二酮。
这些和其他RXR调节剂公开在WO 0116122和WO 0116123中,属于Maxia Pharmaceuticals,Inc.。这些出版物也描述了制备和使用RXR调节剂的材料且在此引入作为参考。
D.其他抗糖尿病药物
可以用作本发明第三抗糖尿病药物的抗糖尿病药物包括,但不限于:
(A)噻唑烷二酮类和非噻唑烷二酮胰岛素致敏物,它通过提高胰岛素在靶器官和组织的效应降低外周胰岛素抗性。
已知这些药物中的一些结合并激活核受体过氧化物酶体增殖子火化受体γ(PPAγ),其增强了特应性胰岛素反应基因的转录。RRAR-γ激动剂的实例是噻唑烷二酮类例如:
(1)罗格列酮(rosiglitazone)(2,4-噻唑烷二酮,5-((4-(2-(甲基-2-吡啶基氨基)乙氧基)苯基)甲基-,(Z)-2-丁烯二酸酯(1∶1)或5-((4-(2-(甲基-2-吡啶基氨基)乙氧基)苯基)甲基)-2,4-噻唑烷二酮,称作AVANDIA;也称作BRL49653、BRL 49653C、BRL 49653c、SB 210232,或罗格列酮马来酸盐);
(2)吡格列酮(2,4-噻唑烷二酮,5-((4-(2-(5-乙基-2-吡啶基)乙氧基)苯基)甲基)-,一氯化氢,(+-)-或5-((4-(2-(5-乙基-2-吡啶基)乙氧基)苯基)甲基)-2,4-随我在二酮,称作ACTOS、ZACTOS,或GLUSTIN;也称作AD 4833,U 72107,U72107A,U72107E,吡格列酮盐酸盐(USAN));
(3)曲格列酮(5-((3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基)苯基)甲基)2,4-噻唑烷二酮,称作NOSCAL、REZULIN、ROMOZIN,或PRELAY;也称作CI 991,CS045,GR92132,GR92132X);
(4)伊格列酮(isaglitazone)((+)5-[[6-[(2-氟苯基)甲氧基]-2-萘基]甲基]-2,4-噻唑烷二酮或5-((6-((2-氟苯基)甲氧基)-2-萘基)甲基-2,4-噻唑烷二酮或5-(6-(2-氟苄氧基)萘-2-基甲基)噻唑烷-2,4-二酮,也称作MCC-555或neoglitezone);和
(5)5-BTZD。
此外,用作胰岛素致敏剂的非噻唑烷二酮类包括,但不限于:
(1)JT-501(JTT 501,PNU-1827,PNU-716-MET-0096,或PNU182716:异噁唑烷-3,5-二酮,4-((4-(2-苯基-5-甲基)-1,3-噁唑基)以及苯基-4)甲基-);
(2)KRP-297(5-(2,4-二氧杂噻唑烷-5-基甲基)-2-甲氧基-N-(4-(三氟甲基)苄基)苯甲酰胺或5-((2,4-二氧代-5-噻唑烷基)甲基)-2-甲氧基-N-((4-(三氟甲基)苯基)甲基)苯甲酰胺);和
(3)farglitazar(L-酪氨酸,N-(2-苯甲酰基苯基)-o-(2-(5-甲基-2-苯基-4-噁唑基)乙基)-或N-(2-苯甲酰基苯基)-O-(2-(5-甲基-2-苯基-4-噁唑基)乙基)-L-酪氨酸,或GW2570或GI-262570)。
其他药物也被证明具有PPAR调节活性,例如PPARγ、SPPAγR和/或PPARα激动剂活性。实例如下:
(1)AD5075;
(2)R 119702((+-)-5-(4-(5-甲氧基-1H-苯并咪唑-2-基甲氧基)苄基)噻唑烷-2,4-二酮盐酸盐,或CI 1037或CS 011);
(3)CLX-0940(过氧化物酶体增殖子活化受体α激动剂/过氧化物酶体增殖子活化受体γ激动剂)
(4)LR-90(2,5,5-三(4-氯苯基)-1,3-二噁烷-2-甲酸,PPARγ激动剂);
(5)Tularik(PPARγ激动剂);
(6)CLX-0921(PPARγ激动剂);
(7)CGP-52608(PPAR激动剂);
(8)GW-409890(PPAR激动剂);
(9)GW-7845(PPAR激动剂);
(10)L-764406(PPAR激动剂);
(11)LG-101280(PPAR激动剂);
(12)LM-4156(PPAR激动剂);
(13)Risarestat(CT-112);
(14)YM 440(PPAR激动剂);
(15)AR-H049020(PPAR激动剂);
(16)GW 0072(4-(4-((2S,5S)-5-(2-(二(苯基甲基)氨基)-2-氧代乙基)-2-庚基-4-氧代-3-噻唑烷基)丁基)苯甲酸);
(17)GW 409544(GW-544或GW-409544);
(18)NN 2344(DRF 2593);
(19)NN 622(DRF 2725);
(20)AR-H039242(AZ-242);
(21)GW 9820(fibrate);
(22)GW 1929(N-(2-苯甲酰基苯基)-O-(2-(甲基-2-吡啶基氨基)乙基)-L-酪氨酸,称作GW 2331,PPARα/γ激动剂);
(23)SB 219994((S)-4-(2-(2-苯并噁唑基甲基氨基)乙氧基)α-(2,2,2-三氟乙氧基)苯丙酸或3-(4--(2-(N-(2-苯并噁唑基)-N-甲基氨基)乙氧基)苯基)-2(S)(2,2,2-三氟乙氧基)丙酸或苯丙酸,4(2-(2-苯并噁唑基甲基氨基)乙氧基)-α-(2,2,2-三氟乙氧基)-,(αS)-,PPARα/γ激动剂);
(24)L-796449(PPARα/γ激动剂);
(25)非诺贝特(丙酸,2-[4-(4-氯苯甲酰基)苯氧基]-2-甲基-,1-甲基乙脂,称作TRICOR,LIPCOR,LIPANTIL,LIPIDIL MICROPPARα激动剂);
(26)GW-9578(PPARα激动剂);
(27)GW-2433(PPARα/γ激动剂);
(28)GW-0207(PPARγ激动剂);
(29)LG-100641(PPARγ激动剂);
(30)LY-300512(PPARγ激动剂);
(31)NID525-209(NID-525);
(32)VDO-52(VDO-52);
(33)LG 100754(过氧化物酶体增殖子活化的受体激动剂);
(34)LY-510929(过氧化物酶体增殖子活化的受体激动剂);
(35)bexarotene(4-(1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙炔基)苯甲酸,称作TARGRETIN,TARGRETYN,TARGREXIN;也称作LGD 1069,LG 100069,LG 1069,LDG 1069,LG 69,RO 264455);将
(36)GW-1536(PPARα/γ激动剂)。
(B)其他胰岛素致敏剂包括,但不限于:
(1)INS-1(D-手性肌醇或D-1,2,3,4,5,6-六羟基环己烷);
(2)蛋白酪氨酸磷酸酶1B(PTP-1B)抑制剂;
(3)糖原合酶激酶-3(GSK3)抑制剂;
(4)β3肾上腺受体激动剂例如ZD 2079((R)-N-(2-(4-(羧甲基)苯氧基)乙基)-N-(2-羟基-2-苯乙基)氯化铵,也称作ICI D 2079)或AZ 40140;
(5)糖原磷酸化酶抑制剂;
(6)果糖-1,6-二磷酸酶抑制剂;
(7)吡啶甲酸铬,氧钒基硫酸盐(羟基硫酸钒);
(8)KP 102(有机钒化合物);
(9)聚烟酸铬盐;
(10)钾通道激动剂NN 414;
(11)YM 268(5,5′-亚甲基-二(1,4-亚苯基)二亚甲基二(噻唑烷-2,4-二酮);
(12)TS 971;
(13)T 174((+-)-5-(2,4-二氧代噻唑烷-5-基甲基)-2-(2-萘基甲基)苯并噁唑);
(14)SDZ PGU 693((+)-反式-2(S-((4-氯苯氧基)甲基)-7α-(3,4-二氯苯基)四氢吡咯并(2,1-b)噁唑-5(6H)-酮);
(15)S 15261((-)-4-(2-((9H-芴-9-基乙酰基)氨基)乙基)苯甲酸-2-((2-甲氧基-2-(3-(三氟甲基)苯基)乙基)氨基)乙酯);
(16)AZM 134(Alizyme);
(17)ARIAD;
(18)R 102380;
(19)PNU 140975(1-(肼基亚氨基甲基)肼基)乙酸;
(20)PNU 106817(2-(肼基亚氨基甲基)肼基)乙酸;
(21)NC 2100(5-((7-(苯基甲氧基)-3-喹啉基)甲基)-2,4-噻唑烷二酮;
(22)MXC 3255;
(23)MBX 102;
(24)ALT 4037;
(25)AM 454;
(26)JTP 20993(2-(4-(2-(5-甲基-2-苯基-4-噁唑基)乙氧基)苄基)-丙二酸二甲基二酯);
(27)Dexlipotam(5(R)-(1,2-二硫杂环戊烷-3-基)戊酸,也称作(R)-α硫辛酸或(R)-硫辛酸);
(28)BM 170744(2,2-二氯-12-(对氯苯基)十二烷酸);
(29)BM 152054(5-(4-(2-(5-甲基-2-(2-噻吩基)噁唑-4-基)乙氧基)苯并噻吩-7-基甲基)噻唑烷-2,4-二酮);
(30)BM 131258(5-(4-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苯并噻吩-7-基甲基)噻唑烷-2,4-二酮);
(31)CRE 16336(EML 16336);
(32)HQL 975(3-(4-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苯基)-2(S)-(丙基氨基)丙酸);
(33)DRF 2189(5-((4-(2-(1-吲哚基)乙氧基)苯基)甲基)噻唑烷-2,4-二酮);
(34)DRF 554158;
(35)DRF-NPCC;
(36)CLX 0100,CLX 0101,CLX 0900,或CLX 0901;
(37)IkappaB激酶(IKK B)抑制剂
(38)促细胞分裂剂活化蛋白激酶(MAPK)抑制剂p38 MAPK刺激物
(39)磷脂酰肌醇三磷酸酯
(40)胰岛素再循环受体抑制剂
(41)葡萄糖转运蛋白4调节剂
(42)TNF-α拮抗剂
(43)血浆细胞分化抗原-1(PC-1)拮抗剂
(44)脂肪细胞脂质结合蛋白(ALBP/aP2)抑制剂
(45)磷酸聚糖
(46)Galparan;
(47)Receptron;
(48)胰岛细胞成熟因子;
(49)胰岛素强化因子(IPF或胰岛素强化因子-1);
(50)与结合蛋白偶联的促生长因子C(还称作IGF BP3,IGF-BP3,SomatoKine);
(51)Diab II(称作V-411)或Glucanin,由Biotech Holdings Ltd.或Volque Pharmaceutical生产;
(52)葡萄糖-6磷酸酶抑制剂;
(53)脂肪酸葡萄糖转运蛋白;
(54)糖皮质激素受体拮抗剂;和
(55)谷氨酰胺:果糖-6-磷酸酰胺转移酶(GFAT)调节剂。
(C)双胍类,它们减少肝糖生产并提高葡萄糖的摄取。实例包括二甲双胍例如:
(1)1,1-二甲基双胍(例如,二甲双胍-DepoMed,二甲双胍-BiovailCorporation,或二甲双胍GR(二甲双胍胃保留聚合物)) ;和
(2)二甲双胍盐酸盐(N,N-二甲基亚氨基二亚酰胺基二酰胺一盐酸盐,也称作LA 6023,BMS 207150,GLUCOPHAGE,或GLUCOPHAGE XR。
(D)α-糖苷酶抑制剂,它抑制α-糖苷酶。α-糖苷酶将果糖转化为葡萄糖,由此延迟碳水化合物的消化。未消化的碳水化合物随后在肠内分解,降低餐后葡萄糖峰。实例包括,但不限于:
(1)阿卡糖(D-葡萄糖,O-4,6-二脱氧-4-(((1S-(1α,4α,5β,6α))-4,5,6-三羟基-3-(羟基甲基)-2-环己烯-1-基)氨基)-α-D-吡喃葡萄糖基-(1-4)-O-α-D-吡喃葡萄糖基-(1-4)-,也称作AG-5421,Bay-g-542,BAY-g-542,GLUCOBAY,PRECOSE,GLUCOR,PRANDASE,GLUMIDA,或ASCAROSE);
(2)米格列醇(3,4,5-哌啶三醇,1-(2-羟基乙基)-2(羟基甲基)-,(2R(2α,3β,4α,5β))-或(2R,3R,4R,5S)-1-(2-羟基乙基)-2-(羟基甲基-3,4,5-哌啶三醇,也称作BAY 1099,BAY M 1099,BAY-m-1099,BAYGLITOL,DIASTABOL,GLYSET,MIGLIBAY,MITOLBAY,PLUMAROL);
(3)CKD-711(0-4-脱氧-4-((2,3-环氧-3-羟基甲基-4,5,6-三羟基环己烷-1-基)氨基)-α-b-吡喃葡萄糖基-(1-4)-α-D-吡喃葡萄糖基-(1-4)-D-吡喃葡萄糖);
(4)乙格列酯(4-(2-((2R,3R,4R,5S)-3,4,5-三羟基-2(羟基甲基)-1-哌啶基)乙氧基)苯甲酸乙基酯,也称作BAY o 1248或MKC 542);
(5)MOR 14(3,4,5-哌啶三醇,2-(羟基甲基)-1-甲基-,(2R-(2α,3β,4α,5β))-,也称作N-甲基脱氧jirimycin或N-甲基moranoline);和
(6)伏格列波糖(3,4-二脱氧-4-((2-羟基-1-(羟基甲基)乙基)氨基)-2-C-(羟基甲基)-D-表-肌醇或D-表-肌醇,3,4-二脱氧-4-((2-羟基-1-(羟基甲基)乙基)氨基)-2-C-(羟基甲基)-,也称作A 71100,AO 128,BASEN,GLUSTAT,VOGLISTAT。
(E)胰岛素类包括定时或短效、中效和长效胰岛素,非可注射性或吸入胰岛素,组织选择性胰岛素,葡糖磷酸激酶肽(D-手性肌醇),胰岛素类似物例如在天然氨基酸序列中存在微小差异的胰岛素分子和胰岛素的小分子模拟物(胰岛素模拟物),和核内体调节剂。实例包括,但不限于:
(1)Biota;
(2)LP 100;
(3)(SP-5-21)-氧代二(1-吡咯烷二硫代羧酸-S,S′)钒,
(4)胰岛素aspart(人胰岛素(28B-L-天门冬氨酸)或B28-Asp胰岛素,也称作胰岛素X14,INA-X14,NOVORAPID,NOVOMIX,或NOVOLOG);
(5)胰岛素detemir(人29B-(N6-(1-氧代十四烷基)-L-赖氨酸)-(1A-21A),(1B-29B)-胰岛素或NN 304);
(6)胰岛素lispro(″28B-L-赖氨酸-29B-L-脯氨酸人胰岛素,或Lys(B28),Pro(B29)人胰岛素类似物,也称作lys-pro胰岛素,LY275585,HUMALOG,HUMALOG MIX 75/25,或HUMALOG MIX50/50);
(7)胰岛素glargine(人(A21-甘氨酸,B31-精氨酸,B32精氨酸)胰岛素HOE 901,也称作LANTUS,OPTISULIN);
(8)胰岛素锌混悬剂,长效(Ultralente),也称作HUMULIN U或ULTRALENTE;
(9)胰岛素锌混悬剂(Lente),70%结晶和30%无定形胰岛素活性剂,也称作LENTE ILETIN II,HUMULIN L,或NOVOLIN L;
(10)HUMULIN 50/50(50%中性精蛋白锌胰岛素和50%胰岛素注射剂);
(11)HUMULIN 70/30(70%中性精蛋白锌胰岛素NPH和30%胰岛素注射剂),也称作NOVOLIN 70/30,NOVOLIN 70/30 PenFill,NOVOLIN 70/30预填充的;
(12)中性精蛋白锌胰岛素活性剂例如NPH ILETIN II,NOVOLIN N,NOVOLIN N PenFill,NOVOLIN N Prefilled,HUMULIN N;
(13)定时胰岛素注射剂例如ILETIN II Regular,NOVOLIN R,VELOSULIN BR,NOVOLIN R PenFill,NOVOLIN R预填充的,HUMULIN R,或Regular U-500(浓缩的);
(14)ARIAD;
(15)LY 197535;
(16)L-783281;和
(17)(17)TE-17411。
(F)胰岛素分泌调节剂例如:
(1)高血糖素样肽-1(GLP-1)和其模拟物;
(2)亲葡萄糖-胰岛素性肽(GIP)和其模拟物;
(3)exendin和其模拟物;
(4)二肽基(peptyl)蛋白酶(DPP或DPPIV)抑制剂例如
(4a)DPP-728或LAF 237(2-吡咯烷甲腈,1-(((2-((5-氰基-2-吡啶基)氨基)乙基)氨基)乙酰基),称作NVP-DPP-728,DPP-728A,LAF-237);
(4b)P 3298或P32/98(二-(3N-((2S,3S)-2-氨基-3-甲基-戊酰基)-1,3-噻唑烷)富马酸酯);
(4c)TSL 225(色胺酰基-1,2,3,4-四氢异喹啉-3-羧酸);
(4d)缬氨酸pyrrolidide(valpyr);
(4e)1-氨基烷基异喹啉酮-4-甲酸酯及其类似物;
(4f)SDZ 272-070(1-(L-Valyl)吡咯烷);
(4g)TMC-2A,TMC-2B,或TMC-2C;
(4h)二肽腈类(2-氰基pyrrolodides);
(4i)CD26抑制剂;和
(4j)SDZ 274-444;
(5)高血糖素拮抗剂例如AY-279955;和
(6)糊精激动剂,其包括,但不限于,pramlintide(AC 137,Symlin,三前糊精或pramlintide乙酸酯)。
(G)胰岛素促分泌剂,其通过刺激胰腺β细胞提高胰岛素的生产,例如:
(1)阿格列奈(asmitiglinide)((2(S)-顺)-八氢-γ-氧代-α-(苯基甲基)-2H-异吲哚-2-丁酸,钙盐,也称作mituglimide钙水合物,KAD 1229,或S21403);
(2)Ro 34563;
(3)那格列奈(nateglinide)(反式-N-((4-(1-甲基乙基)环己基)羰基)D-苯丙氨酸,也称作A 4166,AY 4166,YM 026,FOX 988,DJN 608,SDZ DJN608,STARLIX,STARSIS,FASTIC,TRAZEC);
(4)JTT 608(反式-4-甲基-γ-氧代环己烷丁酸;
(5)磺酰脲类例如:
(5a)氯磺丙脲(1-[(p-氯苯基)磺酰基]-3-丙基脲,也称作DIABINESE);
(5b)妥拉磺脲(TOLINASE或TOLANASE);
(5c)甲苯磺丁脲(ORINASE或RASTINON);
(5d)格列本脲(1-[[p-[2-(5-氯-o-茴香酰氨基(anisamido))乙基]苯基]磺酰基]-3-环己基脲,也称作Glibenclamide,DIAβ,MICRONASE,GLYNASE PresTab,或DAONIL);
(5e)格列吡嗪(1-环己基-3-[[p-[2-(5-乙基吡嗪甲酰氨基)乙基]苯基]磺酰基]脲,也称作GLUCOTROL,GLUCOTROL XL,MINODIAB,或GLIBENESE);
(5f)格列美脲(1H-吡咯-1-甲酰胺,3-乙基-2,5-二氢-4-甲基-N-[2-[4-[[[[(4-甲基环己基)氨基]羰基]氨基]磺酰基]苯基]乙基]-2-氧代-,反式-,也称作Hoe-490或AMARYL);
(5g)醋酸己脲(DYMELOR);
(5h)格列齐特(DIAMICRON);
(5i)格列戊脲(STATICUM);
(5j)格列喹酮(GLURENORM);和
(5k)格列索脲(DIABENOR);
(6)K+通道阻滞剂包括,但不限于,meglitinides例如
(6a)瑞格列奈((S)-2-乙氧基-4-(2-((3-甲基-1-(2-(1哌啶基)苯基)丁基)氨基)-2-氧代乙基)苯甲酸,也称作AGEE 623,AGEE 623 ZW,NN 623,PRANDIN,或NovoNorm);
(6b)咪唑啉类;和
(6c)α-2肾上腺受体拮抗剂;
(7)脑垂体腺苷酸环化酶激活多肽(PAcAP);
(8)血管活性肠肽(VIP);
(9)氨基酸类似物;和
(10)葡糖激酶激活剂。
(H)生长因子例如:
(1)胰岛素样生长因子(IGF-1,IGF-2);
(2)小分子神经营养因子类;
(3)生长抑素;
(4)生长激素释放肽(GHRP);
(5)生长激素释放因子(GHRF);和
(6)人生长激素片段。
(I)免疫调节剂例如:
(1)疫苗;
(2)T-细胞抑制剂
(3)单颗粒抗体;
(4)白介素-1(IL-1)拮抗剂;和
(5)(5)BDNF。
(J)其他抗糖尿病药物:
(1)rHu-高血糖素;
(2)DHEA类似物;
(3)肉毒碱棕榈酰转移酶(CPT)抑制剂;
(4)胰岛神经发生;
(5)胰腺β淀粉样抑制剂;和
(6)UCP(未偶联的蛋白)-2和UCP-3调节剂。
此外,在上述部分C中描述的第二RXR调节剂也可以用作第三抗糖尿病药物,条件是它不同于第一RXR调节剂。
E.联合形式
本发明特征在于包括施用葡萄糖重吸收抑制剂(例如SGLT抑制剂)和RXR调节剂来治疗糖尿病和X综合征,和其有关的症状或并发症的联合治疗。SGLT抑制剂在许多NIDDM的模型中证实的功效确定了这种药物单用在治疗人体的NIDDM中的可利用性。由于葡萄糖重吸收抑制剂具有不同于RXR调节剂的作用机理,所以与RXR调节剂的联合具有减少获得合并治疗或药物效价所需的任一药物的用量的优点,这是相对于任一药物单用而言,由此减轻了一种或多种不良副作用,其常常包括体重增加、水肿、心肌肥大、肝脏肥大、低血糖,或肝中毒,或其任何组合。
本发明提供一种用于治疗对象中的糖尿病或X综合征,或其有关症状或并发症的方法,钙方法包括给钙对象施用合用有效量的葡萄糖重吸收抑制剂和合用有效量的RXR调节剂。在本发明的一个方面,所述的RXR调节剂是提高对象中的胰岛素敏感性的RXR激动剂。在本发明的另一方面,所述的RXR调节剂是提供对象中的胰岛素敏感性的RXR拮抗剂。判断药物的胰岛素致敏活性的方法是所属领域公知的。譬如,胰岛素致敏物可以在口服葡萄糖耐受试验中提高对象的葡萄糖耐受性。
特别是,糖尿病或X综合征,或其有关症状或并发症选自IDDM、MIDDM、IGT,和IFG。更具体地,所述的RXR调节剂式VI的化合物,
其中R1,R2,R3,R4,R5,A,Ar,m,n,W,X,Y,和Z如上述部分C所述。
当n是1时,优选R1和R2与它们所连的芳环一起构成选择性含有1或2个选自O、S、NH或N-烷基的杂原子的取代的环烷基,和R3是烷基或取代的烷基。另外优选,A是-CR6R7其中R6和R7独立地或一起是烷基;或R6和R7一起构成含有1或2个氧原子的环烷基并且更优选1,3-二氧杂环戊烷。还优选,基团是2,4-噻唑烷二酮、2-硫代-4-噻唑烷二酮、异噁唑烷二酮、2,4-咪唑烷二酮或2,4-咪唑烷二酮。
优选式VI的化合物选自:
3-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-4-三氟甲氧基亚苄基-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]亚苄基-2,4-咪唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]亚苄基-2,4-咪唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2-硫代-2,4-噻唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2-硫代-2 ,4-噻唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2-硫代-2,4-咪唑烷二酮;
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2-硫代-2,4-咪唑烷二酮;
4-[2-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-1,3-二氧杂环戊烷]苄基-2,4-咪唑烷二酮;和
4-[2-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-2-丙基]苄基-2,4-咪唑烷二酮。
式VI的优选化合物之一是MX-6054,其是2,4-噻唑烷二酮,5[[5,6,7,8-四氢-3,5,5,5,8,8-五甲基-2-萘基]-4-(三氟甲氧基)苯基]亚甲基]-,(5Z),也称作3-(3,5,5,8,8,-五甲基-5,6,7,8-四氢-2-萘基)4-三氟甲氧基亚苄基-2,4-噻唑烷二酮,如下式所示:
本发明还提供含有一种或多种葡萄糖重吸收抑制剂、一种或多种RXR调节剂和药学可接受载体的药物组合物。在本发明的一个方面,述的RXR调节剂是提高对象中的胰岛素敏感性的RXR激动剂。在本发明的另一方面,所述的RXR调节剂是提供对象中的胰岛素敏感性的RXR拮抗剂。
具体地,所述的葡萄糖重吸收抑制剂是式V的化合物:
其中
Ar是芳基或杂芳基;
OX是被选择性保护的羟基;
Y是氢或烷基;和
Z是其中吡喃葡萄糖基,其中它的一个或多个羟基可以被一个或多个选自α-D-吡喃葡萄糖基、烷酰基、烷氧基羰基和取代的烷基的基团选择性取代。
优选,Z是β-D-吡喃葡萄糖基。
一组优选的式V化合物是式I的化合物,其中取代基如美国专利NO 6048842所述,特别是权利要求2至10。
一组优选的式V化合物是式II的化合物,其中取代基如美国专利NO 5830873所述,特别是权利要求2至8和13和16。
一组优选的式V化合物是式III的化合物,其中取代基如美国专利NO 5767094所述,特别是权利要求2、3、8和9。
一组优选的式V化合物是式IV的化合物,其中取代基如美国专利NO5731292和5424406所述,特别是美国专利NO的权利要求4-135731292和美国专利NO 5424406的权利要求6-13和15-18。
优选地,所述的葡萄糖重吸收抑制剂选自T-1095和T-1095A。
T-1095A在肾脏中是SGLT的选择性和有效抑制剂。T-1095是前药且在肝脏内转化为其活性形式T-1095A。已经证实T-1095的口服给药通过在IDDM和NIDDM的啮齿动物模型中增强葡萄糖的排泄作用从而抑制升高的血糖水平。用T-1095处理3个周至6个月可以减少糖尿病啮齿动物模型中的饮食和禁食血糖水平和HbA1c(链尿霉素(STZ)诱发的糖尿病大鼠,黄色KK小鼠,db/对比小鼠,Zucker糖尿病脂肪大鼠和GK大鼠)。此外,在黄色KK小鼠和其他糖尿病小鼠模型中减轻了高胰岛素血症、高甘油三酯血症,和微蛋白尿的恶化。口服葡萄糖耐受试验和高胰岛素血症euglycemic钳研究的结果揭示出葡萄糖耐受性的改善和胰岛素抗性的减轻。在用T-1095处理过程中观察到没有体重增加、尿道感染、血浆电解质失衡、食物摄取改变、急性低血糖休克和肾脏病变的迹象。碳酸酯的存在可以提供SGLT选择性。对于肠内SGLT-1,T-1095A是比T-1095更好的底物。该前药体内水解生成T-1096A,它也是在肾脏中抑制SGLT-1的更好底物。
T-1095或T-1095A可以用一个或多个羟基或二醇保护基保护,例如上述部分A所述的那些。
为了应用到药物中,式I、II、III、IV或V的化合物的盐是指无毒“药学可接受盐”。然而,其他盐可以用于制备本发明的化合物或制备其药学可接受盐。代表性有机或无机酸包括,但不限于,盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、羟基乙酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、羟基乙磺酸、苯磺酸、草酸、扑酸、2-萘磺酸、队甲苯磺酸、环己烷氨基磺酸、水杨酸、糖精酸或三氟乙酸。代表性碱性/阳离子盐包括,但不限于,苄星青霉素、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺、普鲁卡因、铝、钙、锂、镁、钾、钠或锌。式I、II、III、IV或V的化合物或其药学可接受盐,可以包括其分子内盐,或其溶剂化物或水合物。
F.给药、制剂和剂量
所述化合物、组合物和联合形式在治疗葡萄糖和脂质代谢疾病中的效用可以按照所属领域熟知的方法测定(参见下列参考文献),和美国专利No5424406、5731292、5767094、5830873和6048842,其在此引入作为参考。所述的化合物可以通过任何常规给药途径给药,包括,但不限于,静脉内、口服、皮下、肌肉内、皮内和非肠道给药。优选地,制剂用于口服给药。
本发明还提供含有一种或多种葡萄糖重吸收抑制剂和一种或多种RXR调节剂以及药物可接受载体的药物组合物。
产品的剂量对于每个成年人来说在1-1000mg/天的宽范围内变化。对于口服给药,组合物优选以含有0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0 25.0,50.0,100,150,200,250或500mg活性成分的片剂形式提供给被治疗患者用于症状调整。所述的化合物以每天1-2次的方案给药。然而,剂量可以根据患者的需要、被治疗病症的严重性和所用化合物改变。可以利用每天给药或周期后给药。优选这些组合物是单位剂型例如片剂、丸剂、胶囊剂、散剂、颗粒剂、灭菌非肠道溶液或混悬剂、计量气雾剂或液体喷雾剂、滴剂、安瓿剂、自注射装置或栓剂;用于口服、非肠道、鼻内、舌下或直肠给药,或用于吸入或喷入给药。或者,所述的组合物可以以适合每周给药一次或每月给药一次的形式存在;譬如,活性化合物的不溶性盐,如癸酸盐,可以用来为肌肉内注射提供延效型制剂。微粒制备固体组合物例如片剂,将主要的一种或多种活性成分与药物载体,例如常规制片组分如玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙或树胶,和其他药物稀释剂如水,混合,形成含有一种或多种葡萄糖重吸收抑制剂和一种或多种RXR调节剂或其药学可接受盐的均匀混合物的固体预形成组合物。当提及这些预形成组合物为均匀时,是指一种或多种活性成分均匀分散在整个组合物中使该组合物可以容易地细分为等效剂型如片剂、丸剂和胶囊。这种固体预形成组合物随后细分为含有0.1-约500mg本发明的活性成分的上述类型的单位剂型。新组合物的片剂或丸剂可以被包衣或者化合得到具有长效作用优点的剂型。譬如,片剂或丸剂可以含有内部剂型和外部剂型组分,后者采取包封在前者外的形式。两种组分可以被肠溶层分开,肠溶层发挥抵抗胃内崩解的作用并且使内部组分完整通过进入到十二指肠内或者延迟释放。许多材料可以用于所述的肠溶层或包衣,例如含有多种聚合酸的材料,此外材料例如是紫胶、鲸蜡醇和醋酸纤维素。
本发明的新组合物可以掺混来经口服或注射给药的液体形式包括,水溶液,适当矫味的糖浆剂,水或油混悬液,和含有可食用油例如棉籽油、芝麻油、椰子油或花生油的矫味乳剂,以及酏剂和类似药学载体。适合于水混悬液的分散或助悬剂,包括合成和天然树胶例如黄芪胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。适当矫味的悬浮或分散剂的液体形式还可以含有合成和天然树胶,例如,黄芪胶、阿拉伯胶、甲基纤维素等。为了非肠道给药,需要灭菌混悬剂和溶液。当需要静脉内给药时采用一般含有适当防腐剂的等渗制剂。
可取地,本发明的一种或多种葡萄糖重吸收抑制剂和一种或多种RXR调节剂的联合形式可以以一个日剂量给药,或者全天剂量可以分为每天2、3或4次给药。此外,本发明一种或多种葡萄糖重吸收抑制剂和/或一种或多种RXR调节剂可以以鼻内形式通过局部使用适当的鼻内载体,或利用所属领域技术人员熟知的透皮贴剂来给药。为了以透皮给药体系的形式给药,显然,在整个给药方案中给药剂量应是连续而不是间断的。
譬如,对于片剂或胶囊形式的口服给药,活性药物组分可以与口服、非毒性药学可接受惰性载体如乙醇、甘油、水等混合。此外,当希望或需要时,适当的粘合剂,润滑剂,崩解剂和着色剂也可以掺混在混合物中。适当的粘合剂包括,不限于,淀粉、明胶、天然糖如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶如阿拉伯胶、黄芪胶或油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,不限于,淀粉、甲基纤维素、琼脂、皂土、黄原胶等。
其中本发明涉及联合形式的给药,所述的化合物可以同时、依次或以单一药物组合物联合给药。当所述的化合物分开给药时,各给药化合物每天的剂量数,可能不一定相同,例如当一种化合物可能具有较大的作用持续时间时,并且因此,给药次数较少。
所属领域技术人员可以很容易判断出最佳给药剂量,并且随着使用的化合物、制剂的强度、给药方式和疾病状况的进展而变化。此外,与被治疗特定患者有关的因素包括患者年龄、体重、饮食和给药时间,由此需要调整剂量。
本发明的新组合物还可以以脂质体给药体系的形式给药,例如小单层囊、大单层囊,和多层囊。脂质体可以由多种脂质形成,包括但不限于两亲性脂质例如磷脂酰胆碱、鞘磷脂、磷脂酰乙醇胺类、磷脂酰胆碱联、心磷脂、磷脂酰丝氨酸类、磷脂酰甘油类、磷脂酸类、磷脂酰肌醇、二酰基三甲基丙烯铵类、二酰基二甲基丙烷铵类,和硬脂胺、天然脂质如甘油三酯,和它们的联合形式。它们可以含有胆甾醇或可以是不含有胆甾醇的。
对于式V、VI和其他公开的结构式,显然本发明组合物中的一些化合物可以在其结构中具有一个或多个不对称碳原子。本发明在其范围内包括该化合物的立体化学纯异构体及其外消旋体。立体化学纯异构体可以通过采用现有已知原理来获得。非对映异构体可以通过物理分离法分离,例如分级解决和色谱技术,并且对映异构体可以通过用光学活性酸或碱选择性结晶非对映异构盐或通过手性色谱经将彼此分开。纯立体异构体还可以由适当的立体化学纯起始原料合成制备,或者利用立体特异性反应制备。
本发明组合物中的一些化合物可以具有多种独立异构体,例如反式和顺式,和多种α和β连接(在图平面所下方和上方)。此外,当制备本发明化合物的方法得到立体异构体的混合物时,可以通过常规技术分离这些异构体,例如制备色谱。所述的化合物可以制备为单一立体异构体或者外消旋体成为一些可能立体异构体的混合物。通过合成或拆分可以得到非外消旋形式。所述的混合物可以,例如,通过标准技术拆分为其组分对映异构体,例如通过成盐形成非对映异构体对。所述的化合物还可以通过与手性辅剂共价连接、随后色谱分离和/或结晶分离,并且除去手性辅剂来拆分。或者,所述的化合物可以利用手性色谱拆分。除非另外说明,本发明的范围概括了所有异构体或立体异构体本身,以及顺式和反式异构体的混合物,非对映异构体的混合物和对映异构体(旋光异构体)的外消旋混合物。
所述葡萄糖重吸收抑制剂与RXR调节剂联合给药在治疗糖尿病、X综合征或相关症状或并发症中的治疗作用可以通过所属领域的已知方法来证明。SGLT抑制剂和RXR激动剂的联合治疗的下列实例用于举例说明但不限定本发明。
实施例1
对血浆葡萄糖、血浆胰岛素、血浆甘油三酯、血浆游离脂肪酸、肝重量和体重的影响
为了测试T-1095与RXR激动剂联合的作用,雌性db/db小鼠(6-7周龄/Jackson Labs,ME)每天用载体(0.5%甲基纤维素),RXR激动剂如MX-6054(0.1-10mpk(mg/kg)),T-1095(100mpk),或MX-6054加T-1095处理11天。小鼠(n=8只动物/组)经口饲管以10ml/kg体重的体积接受试验化合物或载体。在第1天,给药之前记录体重,并且在第4、8和11天记录体重。末次给药18小时后,称重小鼠并用CO2/O2(70∶30)麻醉。通过后眼窦穿孔将小鼠放血至位于冰上的2mL肝素化聚丙烯管内。此后分析血浆样本的葡萄糖、胰岛素、甘油三酯,和游离脂肪酸。取出肝脏,称重并冷冻。
SGLT抑制剂和RXR激动剂具有截然不同的作用机理。当与T-1095联合给药时在RXR激动剂如MX-6054的较低浓度下可以观察到改进的血糖控制,通过测量血浆葡萄糖、血浆胰岛素、血浆游离脂肪酸,或血浆甘油三酯,或其联合形式。所以,RXR激动剂如MX-6054对上述参数的影响在剂量-反应曲线中的左移可以非常明显。此外,在与SGLT抑制剂一起给药时用RXR激动剂治疗后观察到的体重增加不明显,因为通过减小体重或体重增加证实了SGLT抑制剂对葡萄糖的尿排泄和机体失去卡路里的促进作用。另外,由于SGLT抑制剂促进适度的利尿,用RXR拮抗剂治疗后常观察到的水肿(和水肿性体重增加)可以被减轻或不再存在。减少RXR激动剂如MX-6054获得功效所需要的量可以改善副作用性能。被减轻的副作用可以包括例如脂肪肝、肝重量增高、体重增加、心脏重量增加、水肿、心肌肥大、肝脏肥大、低血糖和肝中毒,或其任何联合形式的病症。
实施例2
对血浆葡萄糖、血浆胰岛素、血浆甘油三酯、血浆游离脂肪酸、
肝重量和体重的影响
为了测试T-1095与RXR激动剂联合的作用,雌性db/db小鼠(6-7周龄/Jackson Labs,ME)每天用载体(0.5%甲基纤维素),RXR激动剂如MX-6054(10mpk),T-1095(3、10、30,或100mpk),或MX-6054加T-1095处理11天。小鼠(n=8只动物/组)经口饲管以10ml/kg体重的体积接受试验化合物或载体。在第1天,给药之前记录体重,并且在第4、8和11天记录体重。末次给药18小时后,称重小鼠并用CO2/O2(70∶30)麻醉。通过后眼窦穿孔将小鼠放血至位于冰上的2mL肝素化聚丙烯管内。此后分析血浆样本的葡萄糖、胰岛素、甘油三酯,和游离脂肪酸。取出肝脏,称重并冷冻。
SGLT抑制剂和RXR激动剂具有截然不同的作用机理。当与SGLT抑制剂联合给药时用RXR激动剂处理后观察到的体重增加不明显,因为通过减少体重或体重增加证实了SGLT抑制剂对葡萄糖的尿排泄和机体失去卡路里的促进作用。另外,由于SGLT抑制剂促进适度的利尿,用RXR拮抗剂治疗后常观察到的水肿(和水肿性体重增加)可以被减轻或不再存在。减少RXR激动剂如MX-6054获得功效所需要的量可以改善副作用性能。被减轻的副作用可以包括例如脂肪肝、肝重量增高、体重增加、心脏重量增加、水肿、心肌肥大、肝脏肥大、低血糖和肝中毒,或其任何联合形式的病症。
实施例3
对血浆葡萄糖、HbA1c、血细胞比容、血浆胰岛素、血浆甘油三酯、血浆游离脂肪酸、总胆固醇、HDL、血浆药物水平、肝重量、心脏重量、脂肪含量和体重的影响
为了测试T-1095与RXR激动剂联合的作用,雄性ZDF大鼠(6周龄GMI)每天用载体(0.5%甲基纤维素),RXR激动剂如MX-6054(0.1mpk-10mpk),T-1095(3-100mpk),或MX-6054加T-1095处理28天。大鼠(n=8只动物/组)经口饲管以2ml/kg体重的体积接受试验化合物或载体。在第1天,给药之前记录体重,并且在研究期间每周记录两次。末次给药之前的当天,使动物禁食。末次给药后1小时,称重大鼠并用CO2/O2(70∶30)麻醉。通过后眼窦穿孔将大鼠放血至位于冰上的2m L肝素化聚丙烯管内。随后大鼠接受葡萄糖刺激(2g/kg p.o)并且置于代谢笼内收集尿(4小时)。随后处死动物并取出附睾脂肪垫、肝脏和心脏,称重并冷冻以进行组织检验。此后分析血浆样本的葡萄糖、HbA1c、胰岛素、血细胞比容、血浆药物水平、总胆固醇、HDL、游离脂肪酸和甘油三酯,测量尿体积和尿糖、蛋白质、摩尔渗透压浓度、电解质(Na、K、Cl)、BUN、肌酸酐。
SGLT抑制剂和RXR激动剂具有截然不同的作用机理。当与T-1095联合给药时在RXR激动剂的较低浓度下可以观察到改进的血糖控制,通过测量血浆葡萄糖、HbA1c、血浆胰岛素,或血浆甘油三酯,或其联合形式。所以,在与SGLT抑制剂一起给药时RXR激动剂对上述参数的影响在剂量-反应曲线中的左移可以非常明显。此外,用RXR激动剂治疗后观察到的体重增加不明显,因为通过减小体重或体重增加证实了SGLT抑制剂对葡萄糖的尿排泄和机体失去卡路里的促进作用。另外,由于SGLT抑制剂促进适度的利尿,用RXR拮抗剂治疗后常观察到的水肿(和水肿性体重增加)可以被减轻或不再存在。这可以通过减小了RXR激动剂诱发的心脏重量增加加以证实。减少RXR激动剂获得功效所需要的量可以改善副作用性能。被减轻的副作用可以包括例如脂肪肝、肝重量增高、体重增加、心脏重量增加、水肿、心肌肥大、肝脏肥大、低血糖和肝中毒,或其任何联合形式的病症。
实施例4
对血浆葡萄糖、HbA1c、血细胞比容、血浆胰岛素、游离脂肪酸、血浆甘油三酯、血浆药物水平、肝重量、心脏重量和体重的影响
为了测试T-1095与RXR激动剂联合的作用,雌性db/db小鼠(6-7周龄/Jackson Labs,ME)每天用载体(0.5%甲基纤维素),RXR激动剂如MX-6054(0.1mpk-10mpk),T-1095(3-100mpk),或MX-6054加T-1095处理28天。小鼠(n=8只动物/组)经口饲管以10ml/kg体重的体积接受试验化合物或载体。在第1天,给药之前记录体重,并且在研究期间每周记录两次。末次给药之前的当天,使动物禁食。末次给药后1小时,称重小鼠并用CO2/O2(70∶30)麻醉。通过后眼窦穿孔将小鼠放血至位于冰上的2mL肝素化聚丙烯管内。随后使小鼠禁食过夜并在接受葡萄糖刺激(2g/kg p.o)之前用尾夹放血。杂刺激后30、60、120和180分钟时收集血液。此后处死动物并取出肝脏和心脏,称重并冷冻以进行组织检验。此后分析血浆样本的葡萄糖、HbA1c、胰岛素、血细胞比容、药物水平、游离脂肪酸和甘油三酯。
SGLT抑制剂和RXR激动剂具有截然不同的作用机理。当与T-1095联合给药时在RXR激动剂的较低浓度下可以观察到改进的血糖控制,通过测量血浆葡萄糖、HbA1c、血浆胰岛素,或血浆甘油三酯,或其联合形式。所以,在与SGLT抑制剂一起给药时RXR激动剂对上述参数的影响在剂量-反应曲线中的左移可以非常明显。此外,当与SGLT抑制剂一起给药时用RXR激动剂治疗后观察到的体重增加不明显,因为通过减小体重或体重增加证实了SGLT抑制剂对葡萄糖的尿排泄和机体失去卡路里的促进作用。另外,由于SGLT抑制剂促进适度的利尿,用RXR拮抗剂治疗后常观察到的水肿(和水肿性体重增加)可以被减轻或不再存在。这可以通过减小了RXR激动剂诱发的心脏重量增加加以证实。减少RXR激动剂获得功效所需要的量可以改善副作用性能。被减轻的副作用可以包括例如脂肪肝、肝重量增高、体重增加、心脏重量增加、水肿、心肌肥大、肝脏肥大、低血糖和肝中毒,或其任何联合形式的病症。
实施例5
对血浆葡萄糖、血浆甘油三酯、肝重量、心脏重量和体重的影响
为了测试T-1095与RXR激动剂联合的作用,雌性db/db小鼠(7周龄/Jackson Labs,ME)每天用载体(0.5%甲基纤维素),RXR激动剂如MX-6054(0.1mpk-10mpk),T-1095(100mpk),或MX-6054加T-1095处理11天。小鼠(n=8只动物/组)经口饲管以10ml/kg体重的体积接受试验化合物或载体。在第1天,给药之前记录体重,并且在第4、8和11天记录体重。末次给药后2小时(第11天),称重小鼠并用CO2/O2(70∶30)麻醉。通过后眼窦穿孔将小鼠放血至位于冰上的2mL肝素化聚丙烯管内。取出肝脏,称重并冷冻。
利用Trinder试剂(Sigma Diagnostics)和GPO-Trinder(SigmaDiagnostics)分析血浆样本的葡萄糖和甘油三酯。
表2:在7-8周龄雌性db/db小鼠中口服给药11天的MX-6054+/-T-1095(100mg/kg)的作用。对血浆葡萄糖和甘油三酯水平的影响
处理 | 葡萄糖(mg/dL)±SEM | 甘油三酯(mg/dL)±SEM |
载体对照 | 368±68 | 248±35 |
0,1mpk MX-6054 | 357±46 | 260±24 |
0,3mpk MX-6054 | 342±41 | 262±25 |
1mpk MX-6054 | 406±57 | 259±28 |
3mpk MX-6054 | 255±42 | 206±24 |
10mpk MX-6054 | 224±13<sup>*</sup> | 189±11 |
0.1mpk MX-6064+100mpkT-1095 | 193±12<sup>**</sup> | 240±24 |
0.3mpk MX-6054+100mpkT-1095 | 228±12<sup>*</sup> | 220±38 |
1mpk MX-6054+100mpkT-1085 | 226±21<sup>*</sup> | 206±29 |
3mpk MX-6054+100mpkT-1095 | 228±18 | 213±13 |
10mpk MX-6054+100mpkT-1095 | 185±16<sup>**</sup> | 141±8<sup>*</sup> |
100mpkT-1095 | 201±9<sup>*</sup> | 186±11 |
*p<0.05相对于载体对照。**p<0.01相对于载体对照
取出肝脏和心脏,称重和冷冻。结果如表3所示。
表3.在6-7周龄雌性db/db小鼠中口服给药35天的MX-6054+/-T-1095的作用。对体重和肝脏重量的影响
载体对照 | -0.7±1.3 | 1.81±0.1 |
0.1mpk MX-6054 | -0.7±0.7 | 1.76±0.11 |
0.3mpk MX-6054 | 0.2±0.4 | 1.93±0.08 |
1mpk MX-6054 | 0.6+0.6 | 1.98±0.09 |
3mpk MX-6054 | -0.8±1.3 | 1.89±0.09 |
10mpk MX-6054 | 2.5±1.1 | 2.38±0.18<sup>*</sup> |
0.1mpk MX-6054+100mpkT-1095 | -0.8±1.3 | 1.71±0.05 |
0.3mpk MX-6054+100mpkT-1095 | -1.6±0.4 | 1.67±0.05 |
1mpk MX-6054+100mpkT-1095 | -1.0±0.9 | 1.74±0.13 |
3mpk MX-6054+100mpkT-1095 | -0.3+0.9 | 1.89±0.11 |
10mpk MX-6054+100mpkT-1095 | -2.4±0.7# | 1.99±0.08# |
100mpkT-1095 | 0.7±0.3 | 1.64±0.07 |
*p<0.05相对于载体,#p<0.001相对于10mpk单独的MX-6054,
##p<0.01相对于10mpk单独的MX-6054
SGLT抑制剂和RXR激动剂具有截然不同的作用机理。当与T-1095联合给药时在RXR激动剂的较低浓度下可以观察到改进的血糖控制,通过测量血浆葡萄糖。具有地,RXR激动剂对血浆葡萄糖的影响在剂量-反应曲线中观察到左移。
上述研究证明,T-1095与RXR调节剂联合的口服给药改善了糖尿病的标志状况,包括血糖,和甘油三酯水平。
此外,当与SGLT抑制剂一起给药时用最高浓度的RXR激动剂治疗后观察到的体重增加不明显,这非常可能归因于SGLT抑制剂促进葡萄糖的尿排泄和机体失去卡路里的性能。用MX-6054治疗还使肝脏重量明显增加,这可通过联合给予T-1095来预防。因此,还可以意外改善的不良副作用例如体重增加、肝重量增高、脂肪肝、肝脏肥大、肝中毒和低血糖或其任何联合形式的病症。
上述实施例可以证明T-1095与RXR调节剂联合的口服给药改善了糖尿病的其他标志状况,包括糖基化血红蛋白(HgbA1C)水平。特别是,与一种或多种RXR调节剂单独给药相比,T-1095与一种或多种RXR调节剂联合的口服给药可以减少体重或体重增加以及肝重量或肝重量增加。
所以,为了治疗糖尿病,特别是II型糖尿病,或X综合征,可以使用式I、II、III、IV或V的化合物与一种或多种RXR调节剂、优选那些提高胰岛素敏感性的RXR激动剂,包括每天施用1次或2次在约25-1000mg范围内的重复口服剂量的式I化合物和合用有效量的重复剂量的一种或多种糖尿病治疗药。所属领域技术人员基于标准剂量指南很容易判断在此所述的RXR调节剂的合用有效量。特别是,所述的联合给药可以有效在对象中实现体重、体重增加、肝重量或肝重量增加的降低。
此外,该方法包括(a)给对象施用合用有效量的葡萄糖重吸收抑制剂;和(b)给该对象施用合用有效量的RXR调节剂,可以用来降低需要其的对象中的体重、体重增加,或肝重量,其中联合给药可以采取任意顺序和提供预期治疗作用的联用有效量。
另外,该方法包括(a)给对象施用合用有效量的葡萄糖重吸收抑制剂;和(b)给该对象施用合用有效量的RXR调节剂,可以用来降低患有糖尿病或X综合征,或其有关症状或并发症的对象中的体重、体重增加,肝治疗或肝重量增加,其中联合给药可以采取任意顺序和提供预期治疗作用的联用有效量。
所属领域技术人员可以很容易地判断最佳给药剂量,并且改变具体使用的化合物、给药方式、制剂的强度和疾病的进步。此外,与被治疗的特定患者有关的因素,包括患者的性别、年龄、体重、饮食、给药时间和并存疾病,致使有必要调整剂量。
虽然上述说明教导了本发明的原则,并且实施例是举例说明的目的,应理解本发明的实践包括所有属于本发明权利要求书及其等同范围内的常规变化方案、适应性方案和/或改进方案。
参考文献
1.Freychet,P.(1990)Pancreatic Hormones.In Hormones frommolecules to disease.Kelly,P.A.,Baulieu,E.E.,eds.,Routledge,Chapman和Hall,New York,NY,491-532.
2.Groop,L.C.(1997)Drug treatment of non-胰岛素-dependentdiabetes mellitus,In Textbook of Diabetes.Pickup,J.C.,Williams,G.Eds.,Blackwell Science.Oxford,UK,1-18.
3.UK Prospective Diabetes Study Group.(1998)Intensive blood-葡萄糖Control with sulfphonylureas或胰岛素compared withconventional treatment和risk if complicatons in patients with type 2diabetes.Lancet 352:837-853.
4.UK Prospective Diabetes Study Group.(1998)Effect of intensiveblood葡萄糖control with二甲双胍on complications in overweightpateints with type 2 diabetes.Lancet 352:854-865.
5.Conway,B.R.和Demarest,K.T.(2000)抑制剂of Sodium-葡萄糖Cotransporter,1095.Filed Feruary 23,2000.
6.Evans,A.J.,和Krentz,A.J(1999)Recent developments和emerging therapies for type 2 diabetes mellitus.Drugs R & D 2:75-94.
7.Day,C.(1999)噻唑烷diones:a new class of antidiabetic drugs.Diabetic Med.(1999),16(3),179-192.
8.Schwartz,S.,Raskin,P.,Fonseaca,V.,和Graveline,J.F.(1998)Effect of troglitazone in胰岛素-treated patients with type 2 diabetes.N.Engl.J.Med.338:861-866.
9.Buse,J.B.,Gumbiner,B.,Mathias,N.P.et al.(1998)Troglltazoneuse in胰岛素Otreated type 2 diabetic patients.The Troglitazone胰岛素study group.Diabetes Care 21:1455-1461.
10.Mukherjee,R.,Davies,P.J.A.,Crombie,D.L.,Dischoff,E.D.,Cesario,R.M.et al(1997)Sensitization of diabetic和obese mice to胰岛素by retinoid X receptor激动剂s.Nature 386:407-410.
11.Consoli,A.(1992)Diabetes Care 15:430-441
12.Gerich,J.E.(1992)Horm.Metab.Res.26:18-21.
13.Nestler,J.E.,Jakubowicz,D.J.,Reamer,P.Et al.(1999)Ovulatory和metabolic effects of D-chiro-肌醇in the polycystic ovarysyndrome.N.Engl.J.Med.340:1314-1320.
Claims (21)
1.葡萄糖重吸收抑制剂和维生素A类-X受体调节剂在制备用于治疗糖尿病、X综合征、或其相关症状或并发症的药物中的用途,其中所述的维生素A类-X受体调节剂是MX-6054,和其中所述的葡萄糖重吸收抑制剂是下式(I)化合物
其中OX是任选被保护的羟基;Y是低级烷基;和Z是α-D-吡喃葡萄糖基,其中一个或多个羟基任选被保护。
2.权利要求1的用途,其中所述糖尿病、X综合征、或其有关症状或并发症选自:IDDM、NIDDM、IGT、IFG、肥胖、肾病、神经病、视网膜病、动脉粥样硬化、多囊性卵巢综合征或多囊性卵巢性综合征、高血压、局部缺血、中风、心脏病、刺激性肠病、炎症和白内障。
3.权利要求1或2的用途,其中所述的糖尿病、X综合征,或其有关症状或并发症是IDDM。
4.权利要求1或2的用途,其中所述的糖尿病、X综合征,或其有关症状或并发症是NIDDM。
5.权利要求1或2的用途,其中所述的糖尿病、X综合征,或其有关症状或并发症是IGT或IFG。
8.权利要求1或2的用途,其中所述的葡萄糖重吸收抑制剂是具有一个或多个羟基或二醇保护基的T-1095或T-1095A,或其光学异构体、对映异构体、非对映异构体、外消旋体或外消旋混合物、酯、或其药学可接受盐。
9.权利要求8的用途,其中所述的葡萄糖重吸收抑制剂是T-1095。
10.权利要求8的用途,其中所述的葡萄糖重吸收抑制剂T-1095A。
11.权利要求8的用途,其中T-1095或T-1095A的共同有效量是10-1000mg。
13.权利要求12的用途,其中所述的发作是指从糖尿病前状态至NIDDM。
14.一种药物组合物,其含有葡萄糖重吸收抑制剂、维生素A类-X受体调节剂和药学可接受载体,其中所述的维生素A类-X受体调节剂是MX-6054,其中所述的葡萄糖重吸收抑制剂是下式(I)化合物
其中OX是羟基,其任选被保护;Y是低级烷基;和Z是β-D-吡喃葡萄糖基,其中一个或多个羟基任选被保护。
17.权利要求16的方法,其中所述的葡萄糖重吸收抑制剂是任选具有一个或多个羟基或二醇保护基的T-1095或T-1095A,或其光学异构体、对映异构体、非对映异构体、外消旋体或外消旋混合物、酯、或其药学可接受盐。
19.权利要求18的方法,其中所述的葡萄糖重吸收抑制剂是任选具有一个或多个羟基或二醇保护基的T-1095或T-1095A,或其光学异构体、对映异构体、非对映异构体、外消旋体或外消旋混合物、酯、或其药学可接受盐。
21.权利要求20的用途,其中所述的葡萄糖重吸收抑制剂是任选具有一个或多个羟基或二醇保护基的T-1095或T-1095A,或其光学异构体、对映异构体、非对映异构体、外消旋体或外消旋混合物、酯、或其药学可接受盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28147901P | 2001-04-04 | 2001-04-04 | |
US60/281,479 | 2001-04-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1511038A CN1511038A (zh) | 2004-07-07 |
CN100384430C true CN100384430C (zh) | 2008-04-30 |
Family
ID=23077475
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB02810482XA Expired - Lifetime CN100384430C (zh) | 2001-04-04 | 2002-04-03 | 含有葡萄糖重吸收抑制剂和维生素a类-x受体调节剂的联合治疗 |
Country Status (11)
Country | Link |
---|---|
US (3) | US6838442B2 (zh) |
EP (1) | EP1392326B1 (zh) |
JP (1) | JP4590158B2 (zh) |
CN (1) | CN100384430C (zh) |
AT (1) | ATE442148T1 (zh) |
CA (1) | CA2443325C (zh) |
DE (1) | DE60233655D1 (zh) |
ES (1) | ES2331561T3 (zh) |
MY (1) | MY148432A (zh) |
TW (1) | TWI345978B (zh) |
WO (1) | WO2002080935A1 (zh) |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI279401B (en) | 1999-08-31 | 2007-04-21 | Incyte San Diego Inc | Heterocyclic derivatives for the treatment of diabetes and other diseases |
EA200300982A1 (ru) | 2001-03-07 | 2004-12-30 | Инсайт Сан Диего, Инк. | Гетероциклические производные для лечения рака и других пролиферативных заболеваний |
CA2473156A1 (en) | 2001-03-08 | 2002-09-19 | Incyte San Diego, Inc. | Rxr activating molecules |
ATE423559T1 (de) * | 2001-04-04 | 2009-03-15 | Ortho Mcneil Janssen Pharm | Kombinationstherapie durch glukoseresorptionshemmer und ppar modulatoren |
EP1270012A1 (en) * | 2001-06-21 | 2003-01-02 | Pfizer Products Inc. | Use of pulmonary administration of insulin for treatment of diabetes |
AU2002352706A1 (en) * | 2001-11-15 | 2003-06-10 | Maxia Pharmaceuticals, Inc. | N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders, cancer, and other diseases |
US7102000B2 (en) * | 2002-03-08 | 2006-09-05 | Incyte San Diego Inc. | Heterocyclic amide derivatives for the treatment of diabetes and other diseases |
US7196108B2 (en) * | 2002-03-08 | 2007-03-27 | Incyte San Diego Inc. | Bicyclic heterocycles for the treatment of diabetes and other diseases |
DE10258008B4 (de) * | 2002-12-12 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | Heterocyclische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
DE10258007B4 (de) | 2002-12-12 | 2006-02-09 | Sanofi-Aventis Deutschland Gmbh | Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
AU2004250994B2 (en) * | 2003-06-27 | 2010-12-02 | Dr. Reddy's Research Foundation | Compositions comprising balaglitazone and further antidiabetic compounds |
CN1319956C (zh) * | 2003-09-12 | 2007-06-06 | 深圳市海粤门生物科技开发有限公司 | 一种噻唑烷二酮的衍生物及其药用制剂的制备方法和应用 |
CN1964706A (zh) * | 2004-03-17 | 2007-05-16 | 拉斯·M·拉森 | 通过抑制视觉周期预防视网膜病 |
DE102006028862A1 (de) | 2006-06-23 | 2007-12-27 | Merck Patent Gmbh | 3-Amino-imidazo[1,2-a]pyridinderivate |
DE102007008420A1 (de) | 2007-02-21 | 2008-08-28 | Merck Patent Gmbh | Benzimidazolderivate |
DE102007048716A1 (de) | 2007-10-11 | 2009-04-23 | Merck Patent Gmbh | Imidazo[1,2-a]pyrimidinderivate |
CN101969944B (zh) * | 2008-01-31 | 2013-04-10 | 安斯泰来制药有限公司 | 脂肪性肝病的治疗用医药组合物 |
DE102008017590A1 (de) | 2008-04-07 | 2009-10-08 | Merck Patent Gmbh | Glucopyranosidderivate |
JP5820269B2 (ja) | 2008-05-22 | 2015-11-24 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | Sglt2阻害剤を使用する高尿酸血症の治療方法およびsglt2阻害剤を含有する組成物 |
AU2009286380B2 (en) | 2008-08-28 | 2011-09-15 | Pfizer Inc. | Dioxa-bicyclo[3.2.1.]octane-2,3,4-triol derivatives |
WO2010141690A2 (en) * | 2009-06-04 | 2010-12-09 | Dara Biosciences, Inc. | Indane analogs and use as pharmaceutical agents and process of making |
US8163704B2 (en) | 2009-10-20 | 2012-04-24 | Novartis Ag | Glycoside derivatives and uses thereof |
AU2010310956B2 (en) | 2009-11-02 | 2014-05-08 | Pfizer Inc. | Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives |
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2014113695A1 (en) | 2013-01-18 | 2014-07-24 | Cornell University | Methods of treating diseases associated with high fat diet and vitamin a deficiency using retinoic acid receptor agonists |
EP2774619B1 (de) | 2013-03-04 | 2016-05-18 | BioActive Food GmbH | Zusammensetzung zur Behandlung von hyperglykämischen Erkrankungen |
EP2944311A1 (de) | 2014-05-16 | 2015-11-18 | BioActive Food GmbH | Kombination von biologisch aktiven Substanzen zur Behandlung von hyperglykämischen Erkrankungen |
PE20210644A1 (es) | 2018-07-19 | 2021-03-23 | Astrazeneca Ab | METODOS DE TRATAMIENTO DE HFpEF EMPLEANDO DAPAGLIFLOZINA Y COMPOSICIONES QUE COMPRENDEN LA MISMA |
WO2022022865A1 (en) | 2020-07-27 | 2022-02-03 | Astrazeneca Ab | Methods of treating chronic kidney disease with dapagliflozin |
EP4315350A1 (en) | 2021-04-01 | 2024-02-07 | AstraZeneca UK Limited | Systems and methods for managing prediabetes with a gliflozin sodium-glucose cotransport 2 inhibitor pharmaceutical composition |
WO2023144722A1 (en) | 2022-01-26 | 2023-08-03 | Astrazeneca Ab | Dapagliflozin for use in the treatment of prediabetes or reducing the risk of developing type 2 diabetes |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997010819A1 (en) * | 1995-09-18 | 1997-03-27 | Ligand Pharmaceuticals Incorporated | Treating niddm with rxr agonists |
WO2001074835A1 (en) * | 2000-03-30 | 2001-10-11 | Bristol-Myers Squibb Company | O-glucosylated benzamide sglt2 inhibitors and method |
WO2001074834A1 (en) * | 2000-03-30 | 2001-10-11 | Bristol-Myers Squibb Company | O-aryl glucoside sglt2 inhibitors and method |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US651003A (en) * | 1899-10-12 | 1900-06-05 | Solomon W Bates | Bicycle-pump. |
JPH0253573A (ja) * | 1988-08-11 | 1990-02-22 | Nippon Riki Kk | ラチェットレンチの製造法 |
US5731299A (en) * | 1992-05-29 | 1998-03-24 | The Procter & Gamble Company | Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
CA2102591C (en) * | 1992-11-12 | 2000-12-26 | Kenji Tsujihara | Hypoglycemic agent |
US5731292A (en) | 1992-11-12 | 1998-03-24 | Tanabe Seiyaku Co., Ltd. | Dihydrochalcone derivatives which are hypoglycemic agents |
JP2906978B2 (ja) * | 1993-02-25 | 1999-06-21 | 田辺製薬株式会社 | 血糖降下剤 |
US6046222A (en) * | 1993-09-15 | 2000-04-04 | Warner-Lambert Company | Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome, gestational diabetes and disease states at risk for progressing to noninsulin-dependent diabetes mellitus |
JP2847695B2 (ja) * | 1994-05-11 | 1999-01-20 | 田辺製薬株式会社 | 血糖降下剤 |
US5830873A (en) * | 1994-05-11 | 1998-11-03 | Tanabe Seiyaku Co., Ltd. | Propiophenone derivative and a process for preparing the same |
JP3059088B2 (ja) * | 1995-11-07 | 2000-07-04 | 田辺製薬株式会社 | プロピオフェノン誘導体およびその製法 |
JP3065235B2 (ja) | 1995-11-07 | 2000-07-17 | 田辺製薬株式会社 | プロピオフェノン誘導体およびその製法 |
US5732199A (en) * | 1996-09-25 | 1998-03-24 | Behavior Tech Computer Corporation | Control method and device of scanner with built-in plug-and-play printer port |
ES2176600T3 (es) * | 1996-12-26 | 2002-12-01 | Tanabe Seiyaku Co | Derivado de la propiofenona y procedimientos para su preparacion. |
JP3055135B2 (ja) * | 1996-12-26 | 2000-06-26 | 田辺製薬株式会社 | プロピオフェノン誘導体及びその製法 |
US6153632A (en) | 1997-02-24 | 2000-11-28 | Rieveley; Robert B. | Method and composition for the treatment of diabetes |
CA2294134A1 (en) | 1997-06-18 | 1998-12-23 | Stephen Alistair Smith | Treatment of diabetes with thiazolidinedione and alpha-glucosidase inhibitor |
JP2000080041A (ja) | 1998-03-09 | 2000-03-21 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
TWI249401B (en) | 1999-04-14 | 2006-02-21 | Takeda Chemical Industries Ltd | Agent for improving ketosis |
AR035016A1 (es) | 1999-08-25 | 2004-04-14 | Takeda Chemical Industries Ltd | Composicion de azol promotor de produccion/secrecion de neurotrofina, compuesto prodroga del mismo, composicion farmaceutica que lo comprende y uso del mismo para preparar esta ultima. |
TWI279401B (en) * | 1999-08-31 | 2007-04-21 | Incyte San Diego Inc | Heterocyclic derivatives for the treatment of diabetes and other diseases |
CA2382480C (en) | 1999-08-31 | 2008-09-30 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
PE20010580A1 (es) | 1999-09-03 | 2001-05-25 | Takeda Chemical Industries Ltd | Composicion farmaceutica para tratar la diabetes |
TW558554B (en) * | 1999-10-29 | 2003-10-21 | Takeda Chemical Industries Ltd | Crystals of oxyiminoalkanoic acid derivative |
JP2001192375A (ja) * | 1999-10-29 | 2001-07-17 | Takeda Chem Ind Ltd | オキシイミノアルカン酸誘導体の結晶 |
IL149493A0 (en) * | 1999-11-10 | 2002-11-10 | Takeda Chemical Industries Ltd | 5-membered n-heterocyclic compounds with hypoglycemic and hypolipidemic activity |
US6686337B2 (en) * | 2000-10-30 | 2004-02-03 | Ortho-Mcneil Pharmaceutical, Inc. | Combination therapy comprising anti-diabetic and anticonvulsant agents |
CA2432145C (en) | 2000-12-28 | 2010-07-13 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and use thereof in medicines |
ATE423559T1 (de) * | 2001-04-04 | 2009-03-15 | Ortho Mcneil Janssen Pharm | Kombinationstherapie durch glukoseresorptionshemmer und ppar modulatoren |
-
2002
- 2002-04-03 EP EP02715273A patent/EP1392326B1/en not_active Expired - Lifetime
- 2002-04-03 WO PCT/US2002/010542 patent/WO2002080935A1/en active Application Filing
- 2002-04-03 DE DE60233655T patent/DE60233655D1/de not_active Expired - Lifetime
- 2002-04-03 CN CNB02810482XA patent/CN100384430C/zh not_active Expired - Lifetime
- 2002-04-03 JP JP2002578974A patent/JP4590158B2/ja not_active Expired - Fee Related
- 2002-04-03 CA CA2443325A patent/CA2443325C/en not_active Expired - Lifetime
- 2002-04-03 AT AT02715273T patent/ATE442148T1/de not_active IP Right Cessation
- 2002-04-03 ES ES02715273T patent/ES2331561T3/es not_active Expired - Lifetime
- 2002-04-03 US US10/115,725 patent/US6838442B2/en not_active Expired - Lifetime
- 2002-04-04 TW TW091106917A patent/TWI345978B/zh not_active IP Right Cessation
- 2002-04-04 MY MYPI20021222A patent/MY148432A/en unknown
-
2003
- 2003-02-24 US US10/372,517 patent/US20030195235A1/en not_active Abandoned
-
2007
- 2007-10-24 US US11/923,187 patent/US8183213B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997010819A1 (en) * | 1995-09-18 | 1997-03-27 | Ligand Pharmaceuticals Incorporated | Treating niddm with rxr agonists |
WO2001074835A1 (en) * | 2000-03-30 | 2001-10-11 | Bristol-Myers Squibb Company | O-glucosylated benzamide sglt2 inhibitors and method |
WO2001074834A1 (en) * | 2000-03-30 | 2001-10-11 | Bristol-Myers Squibb Company | O-aryl glucoside sglt2 inhibitors and method |
Also Published As
Publication number | Publication date |
---|---|
EP1392326A1 (en) | 2004-03-03 |
JP2004529914A (ja) | 2004-09-30 |
CA2443325A1 (en) | 2002-10-17 |
CN1511038A (zh) | 2004-07-07 |
JP4590158B2 (ja) | 2010-12-01 |
DE60233655D1 (de) | 2009-10-22 |
ATE442148T1 (de) | 2009-09-15 |
CA2443325C (en) | 2011-06-14 |
WO2002080935A1 (en) | 2002-10-17 |
EP1392326B1 (en) | 2009-09-09 |
ES2331561T3 (es) | 2010-01-08 |
US8183213B2 (en) | 2012-05-22 |
TWI345978B (en) | 2011-08-01 |
US6838442B2 (en) | 2005-01-04 |
US20030195235A1 (en) | 2003-10-16 |
US20030055091A1 (en) | 2003-03-20 |
MY148432A (en) | 2013-04-30 |
US20090075864A1 (en) | 2009-03-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100384430C (zh) | 含有葡萄糖重吸收抑制剂和维生素a类-x受体调节剂的联合治疗 | |
CN100577175C (zh) | 包括葡萄糖重吸收抑制剂和ppar调节剂的联合疗法 | |
KR20080080220A (ko) | Dpiv 억제제 및 메트포르민 또는 티아졸리딘디온을병용한 2형 당뇨병의 치료 | |
DE69826811T4 (de) | Zusammensetzungen für die Verwendung bei der Behandlung und Prävention von Hyperurikämie | |
KR20090088854A (ko) | 2-6-(3-아미노-피페리딘-엘-일)-3-메틸-2,4-디옥소-3,4-디하이드로-2h-피리미딘-1-일메틸-4-플루오로-벤조니트릴의 용도 | |
CN102209532B (zh) | 减少小而致密的ldl颗粒的方法 | |
RU2358738C2 (ru) | Лекарственные средства для лечения сахарного диабета | |
EP1889618A1 (en) | Combined drug for treating diabetes | |
KR101567660B1 (ko) | 진성 당뇨병을 치료하기 위한 병용제 | |
EP1935424A1 (en) | Pharmaceutical compositions comprising combined antidiabetic substances for use in diabetes mellitus | |
CN104968341B (zh) | Glp1r激动剂和二甲双胍的组合及其在制备治疗2型糖尿病和其他障碍的药物中的用途 | |
TW201521727A (zh) | 使用巴比妥酸鹽衍生物來降低尿酸位準的方法 | |
US10759749B2 (en) | Therapeutic agent for diabetes | |
CN101287467B (zh) | 用于调节Lyn激酶活性和治疗相关病症的方法和制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20080430 |