CA2867348A1 - Treatment of cancer with tor kinase inhibitors - Google Patents

Info

Publication number

CA2867348A1

CA2867348A1 CA2867348A CA2867348A CA2867348A1 CA 2867348 A1 CA2867348 A1 CA 2867348A1 CA 2867348 A CA2867348 A CA 2867348A CA 2867348 A CA2867348 A CA 2867348A CA 2867348 A1 CA2867348 A1 CA 2867348A1

Authority

CA

Canada

Prior art keywords

substituted

pyrazin

unsubstituted

tor kinase

breast cancer

Prior art date

2012-03-15

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 229940043355 kinase inhibitor Drugs 0.000 title claims abstract description 376
• 239000003757 phosphotransferase inhibitor Substances 0.000 title claims abstract description 376
• 206010028980 Neoplasm Diseases 0.000 title claims description 77
• 238000011282 treatment Methods 0.000 title description 30
• 201000011510 cancer Diseases 0.000 title description 9
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims abstract description 396
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims abstract description 396
• 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims abstract description 75
• 208000022679 triple-negative breast carcinoma Diseases 0.000 claims abstract description 75
• 208000027706 hormone receptor-positive breast cancer Diseases 0.000 claims abstract description 74
• 238000000034 method Methods 0.000 claims abstract description 58
• 108010006124 DNA-Activated Protein Kinase Proteins 0.000 claims description 38
• 102000005768 DNA-Activated Protein Kinase Human genes 0.000 claims description 38
• 230000005764 inhibitory process Effects 0.000 claims description 25
• 230000037361 pathway Effects 0.000 claims description 21
• 230000000694 effects Effects 0.000 claims description 20
• 102100022466 Eukaryotic translation initiation factor 4E-binding protein 1 Human genes 0.000 claims description 19
• 108050000946 Eukaryotic translation initiation factor 4E-binding protein 1 Proteins 0.000 claims description 19
• 230000004044 response Effects 0.000 claims description 19
• 108091007960 PI3Ks Proteins 0.000 claims description 18
• 102000038030 PI3Ks Human genes 0.000 claims description 18
• 239000000523 sample Substances 0.000 claims description 16
• 239000012472 biological sample Substances 0.000 claims description 15
• 230000027405 negative regulation of phosphorylation Effects 0.000 claims description 11
• 238000011156 evaluation Methods 0.000 claims description 10
• 230000035772 mutation Effects 0.000 claims description 10
• 230000002018 overexpression Effects 0.000 claims description 9
• 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 8
• 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 8
• YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 8
• 102000014160 PTEN Phosphohydrolase Human genes 0.000 claims description 7
• 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 7
• 230000002401 inhibitory effect Effects 0.000 claims description 7
• 238000012544 monitoring process Methods 0.000 claims description 3
• 230000026731 phosphorylation Effects 0.000 claims description 3
• 238000006366 phosphorylation reaction Methods 0.000 claims description 3
• 239000002552 dosage form Substances 0.000 claims 1
• 230000001678 irradiating effect Effects 0.000 claims 1
• HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 description 236
• 125000003118 aryl group Chemical group 0.000 description 128
• 150000001875 compounds Chemical class 0.000 description 106
• 125000000753 cycloalkyl group Chemical group 0.000 description 98
• 125000000217 alkyl group Chemical group 0.000 description 94
• -1 -isopentyl Chemical group 0.000 description 93
• 125000001072 heteroaryl group Chemical group 0.000 description 78
• 125000004415 heterocyclylalkyl group Chemical group 0.000 description 77
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 71
• 229940125904 compound 1 Drugs 0.000 description 43
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 43
• 210000004027 cell Anatomy 0.000 description 36
• 239000000203 mixture Substances 0.000 description 34
• 125000000623 heterocyclic group Chemical group 0.000 description 32
• 150000003839 salts Chemical class 0.000 description 30
• 125000001424 substituent group Chemical group 0.000 description 30
• 229910052757 nitrogen Inorganic materials 0.000 description 24
• 229940002612 prodrug Drugs 0.000 description 24
• 239000000651 prodrug Substances 0.000 description 24
• 125000003107 substituted aryl group Chemical group 0.000 description 23
• 102000015694 estrogen receptors Human genes 0.000 description 22
• 108010038795 estrogen receptors Proteins 0.000 description 22
• 102000003998 progesterone receptors Human genes 0.000 description 22
• 108090000468 progesterone receptors Proteins 0.000 description 22
• 125000004093 cyano group Chemical group *C#N 0.000 description 21
• 239000012453 solvate Substances 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 229910052736 halogen Inorganic materials 0.000 description 18
• 150000002367 halogens Chemical class 0.000 description 18
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
• 150000003222 pyridines Chemical class 0.000 description 18
• 230000037396 body weight Effects 0.000 description 17
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 17
• 125000003545 alkoxy group Chemical group 0.000 description 16
• 238000003556 assay Methods 0.000 description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
• 238000001990 intravenous administration Methods 0.000 description 15
• 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 14
• 101150029707 ERBB2 gene Proteins 0.000 description 14
• 102000001253 Protein Kinase Human genes 0.000 description 14
• SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 14
• 125000004429 atom Chemical group 0.000 description 14
• SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 14
• 201000010099 disease Diseases 0.000 description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 14
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 14
• 150000002475 indoles Chemical class 0.000 description 14
• 108060006633 protein kinase Proteins 0.000 description 14
• 208000011581 secondary neoplasm Diseases 0.000 description 14
• 206010006187 Breast cancer Diseases 0.000 description 13
• 208000026310 Breast neoplasm Diseases 0.000 description 13
• 238000001574 biopsy Methods 0.000 description 13
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 13
• 125000001624 naphthyl group Chemical group 0.000 description 13
• 125000004076 pyridyl group Chemical group 0.000 description 13
• 239000003826 tablet Substances 0.000 description 12
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 11
• 239000002775 capsule Substances 0.000 description 11
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
• 239000003814 drug Substances 0.000 description 11
• 208000024891 symptom Diseases 0.000 description 11
• 238000012360 testing method Methods 0.000 description 11
• 125000004432 carbon atom Chemical group C* 0.000 description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
• 150000003254 radicals Chemical group 0.000 description 10
• 230000009467 reduction Effects 0.000 description 10
• 230000004614 tumor growth Effects 0.000 description 10
• 108091000080 Phosphotransferase Proteins 0.000 description 9
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 9
• 238000009472 formulation Methods 0.000 description 9
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 9
• 102000020233 phosphotransferase Human genes 0.000 description 9
• 150000003230 pyrimidines Chemical class 0.000 description 9
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
• 230000003247 decreasing effect Effects 0.000 description 8
• 125000003226 pyrazolyl group Chemical group 0.000 description 8
• 239000000243 solution Substances 0.000 description 8
• 229930192474 thiophene Natural products 0.000 description 8
• 150000003577 thiophenes Chemical class 0.000 description 8
• 229920002472 Starch Polymers 0.000 description 7
• 125000003710 aryl alkyl group Chemical group 0.000 description 7
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 7
• 230000003111 delayed effect Effects 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• 125000005842 heteroatom Chemical group 0.000 description 7
• 125000001041 indolyl group Chemical group 0.000 description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
• 125000000714 pyrimidinyl group Chemical group 0.000 description 7
• 235000019698 starch Nutrition 0.000 description 7
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
• 102100023421 Nuclear receptor ROR-gamma Human genes 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
• 238000011161 development Methods 0.000 description 6
• 230000018109 developmental process Effects 0.000 description 6
• 239000003085 diluting agent Substances 0.000 description 6
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
• 231100000371 dose-limiting toxicity Toxicity 0.000 description 6
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 6
• 230000000155 isotopic effect Effects 0.000 description 6
• 239000008194 pharmaceutical composition Substances 0.000 description 6
• 230000002265 prevention Effects 0.000 description 6
• 108090000623 proteins and genes Proteins 0.000 description 6
• 229920006395 saturated elastomer Polymers 0.000 description 6
• 239000008107 starch Substances 0.000 description 6
• 230000004083 survival effect Effects 0.000 description 6
• 125000001425 triazolyl group Chemical group 0.000 description 6
• 239000003981 vehicle Substances 0.000 description 6
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 5
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
• 206010061818 Disease progression Diseases 0.000 description 5
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 5
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
• 229940125782 compound 2 Drugs 0.000 description 5
• 125000004122 cyclic group Chemical group 0.000 description 5
• 206010012601 diabetes mellitus Diseases 0.000 description 5
• 230000005750 disease progression Effects 0.000 description 5
• 125000001188 haloalkyl group Chemical group 0.000 description 5
• 125000005843 halogen group Chemical group 0.000 description 5
• 229910052739 hydrogen Inorganic materials 0.000 description 5
• 239000003112 inhibitor Substances 0.000 description 5
• 150000003053 piperidines Chemical class 0.000 description 5
• 102000004169 proteins and genes Human genes 0.000 description 5
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
• QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 5
• 238000001356 surgical procedure Methods 0.000 description 5
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
• 238000002560 therapeutic procedure Methods 0.000 description 5
• 210000004881 tumor cell Anatomy 0.000 description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
• 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
• 229930195725 Mannitol Natural products 0.000 description 4
• 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 4
• 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 4
• 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 description 4
• 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 4
• 241001465754 Metazoa Species 0.000 description 4
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
• 230000000259 anti-tumor effect Effects 0.000 description 4
• 125000004104 aryloxy group Chemical group 0.000 description 4
• 230000008901 benefit Effects 0.000 description 4
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
• 239000011230 binding agent Substances 0.000 description 4
• 239000008280 blood Substances 0.000 description 4
• 239000004202 carbamide Substances 0.000 description 4
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
• 239000001913 cellulose Substances 0.000 description 4
• 235000010980 cellulose Nutrition 0.000 description 4
• 229920002678 cellulose Polymers 0.000 description 4
• 239000003795 chemical substances by application Substances 0.000 description 4
• RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 description 4
• 238000013461 design Methods 0.000 description 4
• 239000011737 fluorine Substances 0.000 description 4
• 229910052731 fluorine Inorganic materials 0.000 description 4
• 125000002883 imidazolyl group Chemical group 0.000 description 4
• 239000000314 lubricant Substances 0.000 description 4
• 239000000594 mannitol Substances 0.000 description 4
• 235000010355 mannitol Nutrition 0.000 description 4
• 206010061289 metastatic neoplasm Diseases 0.000 description 4
• 229920000609 methyl cellulose Polymers 0.000 description 4
• 239000001923 methylcellulose Substances 0.000 description 4
• 235000010981 methylcellulose Nutrition 0.000 description 4
• 125000002950 monocyclic group Chemical group 0.000 description 4
• 229920001223 polyethylene glycol Polymers 0.000 description 4
• 238000001959 radiotherapy Methods 0.000 description 4
• 238000012216 screening Methods 0.000 description 4
• 230000009291 secondary effect Effects 0.000 description 4
• 210000002966 serum Anatomy 0.000 description 4
• 239000000126 substance Substances 0.000 description 4
• 235000000346 sugar Nutrition 0.000 description 4
• 239000000725 suspension Substances 0.000 description 4
• 231100000419 toxicity Toxicity 0.000 description 4
• 230000001988 toxicity Effects 0.000 description 4
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
• 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 3
• 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
• 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 3
• 206010061309 Neoplasm progression Diseases 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
• 229930006000 Sucrose Natural products 0.000 description 3
• 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 3
• 239000002253 acid Substances 0.000 description 3
• 125000004442 acylamino group Chemical group 0.000 description 3
• 235000010443 alginic acid Nutrition 0.000 description 3
• 229920000615 alginic acid Polymers 0.000 description 3
• 125000003342 alkenyl group Chemical group 0.000 description 3
• 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
• 125000003282 alkyl amino group Chemical group 0.000 description 3
• 230000033115 angiogenesis Effects 0.000 description 3
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 3
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 3
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
• 239000000090 biomarker Substances 0.000 description 3
• 235000010290 biphenyl Nutrition 0.000 description 3
• 239000004305 biphenyl Substances 0.000 description 3
• 210000000601 blood cell Anatomy 0.000 description 3
• 210000000481 breast Anatomy 0.000 description 3
• 239000000872 buffer Substances 0.000 description 3
• 239000001506 calcium phosphate Substances 0.000 description 3
• 235000011010 calcium phosphates Nutrition 0.000 description 3
• 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
• 230000005754 cellular signaling Effects 0.000 description 3
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
• 238000004090 dissolution Methods 0.000 description 3
• 239000003937 drug carrier Substances 0.000 description 3
• 150000002148 esters Chemical class 0.000 description 3
• 125000001153 fluoro group Chemical group F* 0.000 description 3
• 235000013305 food Nutrition 0.000 description 3
• 125000002541 furyl group Chemical group 0.000 description 3
• 229940088597 hormone Drugs 0.000 description 3
• 239000005556 hormone Substances 0.000 description 3
• 150000002431 hydrogen Chemical class 0.000 description 3
• 239000001257 hydrogen Substances 0.000 description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
• 125000000842 isoxazolyl group Chemical group 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
• 125000002757 morpholinyl group Chemical group 0.000 description 3
• 231100000252 nontoxic Toxicity 0.000 description 3
• 230000003000 nontoxic effect Effects 0.000 description 3
• 125000002971 oxazolyl group Chemical group 0.000 description 3
• 239000008188 pellet Substances 0.000 description 3
• 239000000546 pharmaceutical excipient Substances 0.000 description 3
• 239000000843 powder Substances 0.000 description 3
• 125000003373 pyrazinyl group Chemical group 0.000 description 3
• 125000002098 pyridazinyl group Chemical group 0.000 description 3
• 125000000168 pyrrolyl group Chemical group 0.000 description 3
• ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
• 238000011160 research Methods 0.000 description 3
• 125000006413 ring segment Chemical group 0.000 description 3
• 229960002930 sirolimus Drugs 0.000 description 3
• 238000007390 skin biopsy Methods 0.000 description 3
• 239000007858 starting material Substances 0.000 description 3
• 239000005720 sucrose Substances 0.000 description 3
• 239000000829 suppository Substances 0.000 description 3
• 239000000454 talc Substances 0.000 description 3
• 229910052623 talc Inorganic materials 0.000 description 3
• 235000012222 talc Nutrition 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
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
• 125000003831 tetrazolyl group Chemical group 0.000 description 3
• 125000000335 thiazolyl group Chemical group 0.000 description 3
• 125000001544 thienyl group Chemical group 0.000 description 3
• 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 3
• 238000004448 titration Methods 0.000 description 3
• QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
• 230000005751 tumor progression Effects 0.000 description 3
• 231100000402 unacceptable toxicity Toxicity 0.000 description 3
• 229920002554 vinyl polymer Polymers 0.000 description 3
• 239000001993 wax Substances 0.000 description 3
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
• LAQJGAKLLZAETL-UHFFFAOYSA-N 2h-pyrazin-3-one Chemical compound O=C1CN=CC=N1 LAQJGAKLLZAETL-UHFFFAOYSA-N 0.000 description 2
• DOCINCLJNAXZQF-LBPRGKRZSA-N 6-fluoro-3-phenyl-2-[(1s)-1-(7h-purin-6-ylamino)ethyl]quinazolin-4-one Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=NC2=CC=C(F)C=C2C(=O)N1C1=CC=CC=C1 DOCINCLJNAXZQF-LBPRGKRZSA-N 0.000 description 2
• DXHKTHGKGVIGTC-UHFFFAOYSA-N 9-(2-hydroxyethyl)-2-(trifluoromethyl)purine-6-carboxamide Chemical compound NC(=O)C1=NC(C(F)(F)F)=NC2=C1N=CN2CCO DXHKTHGKGVIGTC-UHFFFAOYSA-N 0.000 description 2
• FBECNQNZSXSUKI-UHFFFAOYSA-N 9-(2-hydroxyethyl)-2-prop-1-enylpurine-6-carboxamide Chemical compound CC=CC1=NC(C(N)=O)=C2N=CN(CCO)C2=N1 FBECNQNZSXSUKI-UHFFFAOYSA-N 0.000 description 2
• QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 2
• 206010003571 Astrocytoma Diseases 0.000 description 2
• 206010065869 Astrocytoma, low grade Diseases 0.000 description 2
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
• 239000005711 Benzoic acid Substances 0.000 description 2
• 229940122361 Bisphosphonate Drugs 0.000 description 2
• 101100021265 Caenorhabditis elegans lin-5 gene Proteins 0.000 description 2
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
• ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
• OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 2
• 206010007270 Carcinoid syndrome Diseases 0.000 description 2
• 108090000397 Caspase 3 Proteins 0.000 description 2
• 108090000567 Caspase 7 Proteins 0.000 description 2
• 102100029855 Caspase-3 Human genes 0.000 description 2
• 102100038902 Caspase-7 Human genes 0.000 description 2
• 230000005778 DNA damage Effects 0.000 description 2
• 231100000277 DNA damage Toxicity 0.000 description 2
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
• HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
• 229930091371 Fructose Natural products 0.000 description 2
• 239000005715 Fructose Substances 0.000 description 2
• 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 2
• 108010010803 Gelatin Proteins 0.000 description 2
• 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 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
• 101150097381 Mtor gene Proteins 0.000 description 2
• 241000699666 Mus <mouse, genus> Species 0.000 description 2
• 241000699670 Mus sp. Species 0.000 description 2
• ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
• 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 2
• 150000001204 N-oxides Chemical class 0.000 description 2
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
• 208000006265 Renal cell carcinoma Diseases 0.000 description 2
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
• CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
• ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
• 208000026911 Tuberous sclerosis complex Diseases 0.000 description 2
• PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
• 230000002159 abnormal effect Effects 0.000 description 2
• 230000005856 abnormality Effects 0.000 description 2
• 150000007513 acids Chemical class 0.000 description 2
• 125000005426 adeninyl group Chemical group N1=C(N=C2N=CNC2=C1N)* 0.000 description 2
• 150000001299 aldehydes Chemical class 0.000 description 2
• 125000005262 alkoxyamine group Chemical group 0.000 description 2
• 125000002877 alkyl aryl group Chemical group 0.000 description 2
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 2
• 150000001408 amides Chemical class 0.000 description 2
• 150000001409 amidines Chemical class 0.000 description 2
• 238000004458 analytical method Methods 0.000 description 2
• 238000011319 anticancer therapy Methods 0.000 description 2
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 2
• 239000007864 aqueous solution Substances 0.000 description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
• 125000005602 azabenzimidazolyl group Chemical group 0.000 description 2
• 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 2
• 150000001540 azides Chemical class 0.000 description 2
• 125000005874 benzothiadiazolyl group Chemical group 0.000 description 2
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
• 150000004663 bisphosphonates Chemical class 0.000 description 2
• 125000001246 bromo group Chemical group Br* 0.000 description 2
• 229910000389 calcium phosphate Inorganic materials 0.000 description 2
• 239000001768 carboxy methyl cellulose Substances 0.000 description 2
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
• 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
• 230000004663 cell proliferation Effects 0.000 description 2
• 238000012054 celltiter-glo Methods 0.000 description 2
• 230000033077 cellular process Effects 0.000 description 2
• 238000006243 chemical reaction Methods 0.000 description 2
• 239000007910 chewable tablet Substances 0.000 description 2
• 229940110456 cocoa butter Drugs 0.000 description 2
• 235000019868 cocoa butter Nutrition 0.000 description 2
• DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
• 239000013078 crystal Substances 0.000 description 2
• XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 2
• JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
• AUELWJRRASQDKI-UHFFFAOYSA-N cyclohexyl carbamate Chemical compound NC(=O)OC1CCCCC1 AUELWJRRASQDKI-UHFFFAOYSA-N 0.000 description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
• 230000003831 deregulation Effects 0.000 description 2
• 238000001514 detection method Methods 0.000 description 2
• 229910052805 deuterium Inorganic materials 0.000 description 2
• ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 description 2
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
• 150000002081 enamines Chemical class 0.000 description 2
• 229960005167 everolimus Drugs 0.000 description 2
• 230000007717 exclusion Effects 0.000 description 2
• 239000000796 flavoring agent Substances 0.000 description 2
• 125000000524 functional group Chemical group 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
• 239000008103 glucose Substances 0.000 description 2
• 230000009036 growth inhibition Effects 0.000 description 2
• 229920001903 high density polyethylene Polymers 0.000 description 2
• 239000004700 high-density polyethylene Substances 0.000 description 2
• 150000007857 hydrazones Chemical class 0.000 description 2
• ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
• 125000002632 imidazolidinyl group Chemical group 0.000 description 2
• 125000002636 imidazolinyl group Chemical group 0.000 description 2
• 125000005945 imidazopyridyl group Chemical group 0.000 description 2
• 150000003949 imides Chemical class 0.000 description 2
• 150000002466 imines Chemical class 0.000 description 2
• 230000001771 impaired effect Effects 0.000 description 2
• 230000006872 improvement Effects 0.000 description 2
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
• 208000015181 infectious disease Diseases 0.000 description 2
• 238000011081 inoculation Methods 0.000 description 2
• 239000000543 intermediate Substances 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
• 239000012948 isocyanate Substances 0.000 description 2
• 150000002513 isocyanates Chemical class 0.000 description 2
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
• 150000002540 isothiocyanates Chemical class 0.000 description 2
• 150000002576 ketones Chemical class 0.000 description 2
• 238000004020 luminiscence type Methods 0.000 description 2
• 229910052749 magnesium Inorganic materials 0.000 description 2
• 235000019359 magnesium stearate Nutrition 0.000 description 2
• 230000003211 malignant effect Effects 0.000 description 2
• 230000004060 metabolic process Effects 0.000 description 2
• 208000011645 metastatic carcinoma Diseases 0.000 description 2
• LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
• 150000007522 mineralic acids Chemical class 0.000 description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 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 2
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
• 239000002777 nucleoside Substances 0.000 description 2
• 150000007524 organic acids Chemical class 0.000 description 2
• AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
• 150000002923 oximes Chemical class 0.000 description 2
• 239000001301 oxygen Substances 0.000 description 2
• 229910052760 oxygen Inorganic materials 0.000 description 2
• 238000007911 parenteral administration Methods 0.000 description 2
• 230000036961 partial effect Effects 0.000 description 2
• 125000000394 phosphonato group Chemical group [O-]P([O-])(*)=O 0.000 description 2
• 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
• 125000004193 piperazinyl group Chemical group 0.000 description 2
• 125000005936 piperidyl group Chemical group 0.000 description 2
• 125000003367 polycyclic group Chemical group 0.000 description 2
• 239000011591 potassium Substances 0.000 description 2
• 229910052700 potassium Inorganic materials 0.000 description 2
• 238000002360 preparation method Methods 0.000 description 2
• 238000011321 prophylaxis Methods 0.000 description 2
• QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
• 239000003909 protein kinase inhibitor Substances 0.000 description 2
• 230000009822 protein phosphorylation Effects 0.000 description 2
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
• 125000006085 pyrrolopyridyl group Chemical group 0.000 description 2
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
• 230000002285 radioactive effect Effects 0.000 description 2
• 230000000306 recurrent effect Effects 0.000 description 2
• 230000010076 replication Effects 0.000 description 2
• 238000002271 resection Methods 0.000 description 2
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
• 239000011780 sodium chloride Substances 0.000 description 2
• 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
• 239000007787 solid Substances 0.000 description 2
• 239000002904 solvent Substances 0.000 description 2
• 238000011301 standard therapy Methods 0.000 description 2
• 238000003860 storage Methods 0.000 description 2
• 201000004059 subependymal giant cell astrocytoma Diseases 0.000 description 2
• 239000000758 substrate Substances 0.000 description 2
• 150000008163 sugars Chemical class 0.000 description 2
• 229940124530 sulfonamide Drugs 0.000 description 2
• 150000003456 sulfonamides Chemical class 0.000 description 2
• 150000003457 sulfones Chemical class 0.000 description 2
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
• 229910052717 sulfur Inorganic materials 0.000 description 2
• 239000002511 suppository base Substances 0.000 description 2
• 229940063683 taxotere Drugs 0.000 description 2
• 229960000235 temsirolimus Drugs 0.000 description 2
• QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
• 229940124597 therapeutic agent Drugs 0.000 description 2
• 125000004927 thianaphthalenyl group Chemical group S1C(C=CC2=CC=CC=C12)* 0.000 description 2
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
• 150000003568 thioethers Chemical class 0.000 description 2
• 150000003573 thiols Chemical class 0.000 description 2
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
• 208000009999 tuberous sclerosis Diseases 0.000 description 2
• NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-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
• HCUOEKSZWPGJIM-YBRHCDHNSA-N (e,2e)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical compound COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 description 1
• PGDIPOWQYRAOSK-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)NC2=C1 PGDIPOWQYRAOSK-UHFFFAOYSA-N 0.000 description 1
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
• IPVYMXZYXFFDGW-UHFFFAOYSA-N 1-methylpiperidin-4-ol;hydrochloride Chemical compound Cl.CN1CCC(O)CC1 IPVYMXZYXFFDGW-UHFFFAOYSA-N 0.000 description 1
• XRNLNXMBIPHBES-UHFFFAOYSA-N 2-(3h-benzimidazol-5-yl)-3h-benzimidazole-5-carboxamide Chemical compound C1=C2NC=NC2=CC(C=2NC3=CC=C(C=C3N=2)C(=O)N)=C1 XRNLNXMBIPHBES-UHFFFAOYSA-N 0.000 description 1
• YGKQCJUCIVSDMR-UHFFFAOYSA-N 2-(4-cyanophenyl)-9-(2-methoxyphenyl)-8-oxo-7h-purine-6-carboxamide Chemical compound COC1=CC=CC=C1N1C(=O)NC2=C(C(N)=O)N=C(C=3C=CC(=CC=3)C#N)N=C21 YGKQCJUCIVSDMR-UHFFFAOYSA-N 0.000 description 1
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
• YTXQZTBVBLMJBQ-UHFFFAOYSA-N 2-[4-[3-(cyclohexylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CN=C(NC(=O)N2CC3CCCCC3)C2=N1 YTXQZTBVBLMJBQ-UHFFFAOYSA-N 0.000 description 1
• PPDPUIRKDSCCFN-UHFFFAOYSA-N 2-benzofuran-1,3-diimine Chemical compound C1=CC=C2C(=N)OC(=N)C2=C1 PPDPUIRKDSCCFN-UHFFFAOYSA-N 0.000 description 1
• CZUXUTZOEIRAGY-UHFFFAOYSA-N 2-methyl-8-oxo-9-phenyl-7h-purine-6-carboxamide Chemical compound C12=NC(C)=NC(C(N)=O)=C2NC(=O)N1C1=CC=CC=C1 CZUXUTZOEIRAGY-UHFFFAOYSA-N 0.000 description 1
• 125000005916 2-methylpentyl group Chemical group 0.000 description 1
• DZNQOAQRVHCHDP-UHFFFAOYSA-N 2-phenyl-5h-pyrrolo[3,2-d]pyrimidine-4-carboxamide Chemical compound N=1C=2C=CNC=2C(C(=O)N)=NC=1C1=CC=CC=C1 DZNQOAQRVHCHDP-UHFFFAOYSA-N 0.000 description 1
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
• UBBKJGNWZDGODY-UHFFFAOYSA-N 3-(1-phenylethyl)-5-quinolin-5-yl-[1,3]oxazolo[4,5-b]pyrazin-2-one Chemical compound C12=NC(C=3C4=CC=CN=C4C=CC=3)=CN=C2OC(=O)N1C(C)C1=CC=CC=C1 UBBKJGNWZDGODY-UHFFFAOYSA-N 0.000 description 1
• DYPAWPXIWPUQON-UHFFFAOYSA-N 3-(cyclohexylmethyl)-5-phenyl-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound O=C1NC2=NC=C(C=3C=CC=CC=3)N=C2N1CC1CCCCC1 DYPAWPXIWPUQON-UHFFFAOYSA-N 0.000 description 1
• GXTJPCRFZLLAQY-SECBINFHSA-N 3-[(1r)-1-phenylethyl]-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound C1([C@@H](C)N2C(NC3=NC=CN=C32)=O)=CC=CC=C1 GXTJPCRFZLLAQY-SECBINFHSA-N 0.000 description 1
• GXTJPCRFZLLAQY-VIFPVBQESA-N 3-[(1s)-1-phenylethyl]-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound C1([C@H](C)N2C(NC3=NC=CN=C32)=O)=CC=CC=C1 GXTJPCRFZLLAQY-VIFPVBQESA-N 0.000 description 1
• MXSWRKLSDLYKTI-UHFFFAOYSA-N 3-[3-(cyclohexylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=C3N(CC4CCCCC4)C(=O)NC3=NC=2)=C1 MXSWRKLSDLYKTI-UHFFFAOYSA-N 0.000 description 1
• CAULRINBQQAKSS-UHFFFAOYSA-N 3-[5-[2-(oxan-4-yl)ethyl]-6-oxo-7,8-dihydropyrazino[2,3-b]pyrazin-3-yl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=C3N(CCC4CCOCC4)C(=O)CNC3=NC=2)=C1 CAULRINBQQAKSS-UHFFFAOYSA-N 0.000 description 1
• WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
• IWQLAKJGHRHRQO-UHFFFAOYSA-N 3-[8-[2-(oxan-4-yl)ethyl]-6-oxo-5,7-dihydropyrazino[2,3-b]pyrazin-2-yl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=C3N(CCC4CCOCC4)CC(=O)NC3=NC=2)=C1 IWQLAKJGHRHRQO-UHFFFAOYSA-N 0.000 description 1
• LKZBJBNIHVHKPM-UHFFFAOYSA-N 3-[8-[2-(oxan-4-yl)ethyl]-6-oxo-5,7-dihydropyrazino[2,3-b]pyrazin-2-yl]benzonitrile Chemical compound C12=NC(C=3C=C(C=CC=3)C#N)=CN=C2NC(=O)CN1CCC1CCOCC1 LKZBJBNIHVHKPM-UHFFFAOYSA-N 0.000 description 1
• 125000005917 3-methylpentyl group Chemical group 0.000 description 1
• PUXGYYQRWPJAEL-UHFFFAOYSA-N 4-[2-methoxy-3-(2-morpholin-4-ylethyl)imidazo[4,5-b]pyrazin-5-yl]benzamide;hydrochloride Chemical compound Cl.COC1=NC2=NC=C(C=3C=CC(=CC=3)C(N)=O)N=C2N1CCN1CCOCC1 PUXGYYQRWPJAEL-UHFFFAOYSA-N 0.000 description 1
• JQICHLGPNKWAQP-UHFFFAOYSA-N 4-[3-(cyclohexylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C(NC(=O)N2CC3CCCCC3)C2=N1 JQICHLGPNKWAQP-UHFFFAOYSA-N 0.000 description 1
• LQYQBSQPJJZUBK-UHFFFAOYSA-N 4-[3-(cyclohexylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CN=C(NC(=O)N2CC3CCCCC3)C2=N1 LQYQBSQPJJZUBK-UHFFFAOYSA-N 0.000 description 1
• FMTCJUPVXLEVLA-UHFFFAOYSA-N 4-[3-(cyclohexylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzonitrile Chemical compound O=C1NC2=NC=C(C=3C=CC(=CC=3)C#N)N=C2N1CC1CCCCC1 FMTCJUPVXLEVLA-UHFFFAOYSA-N 0.000 description 1
• GWBVTSUHOJVZIN-UHFFFAOYSA-N 4-[3-(oxan-4-ylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C(NC(=O)N2CC3CCOCC3)C2=N1 GWBVTSUHOJVZIN-UHFFFAOYSA-N 0.000 description 1
• RPMAINMFJQKYRB-UHFFFAOYSA-N 4-[3-[2-(oxan-4-yl)ethyl]-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C(NC(=O)N2CCC3CCOCC3)C2=N1 RPMAINMFJQKYRB-UHFFFAOYSA-N 0.000 description 1
• HCVCMRBZELCKKN-UHFFFAOYSA-N 4-[5-[2-(oxan-4-yl)ethyl]-6-oxo-7,8-dihydropyrazino[2,3-b]pyrazin-3-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C(NCC(=O)N2CCC3CCOCC3)C2=N1 HCVCMRBZELCKKN-UHFFFAOYSA-N 0.000 description 1
• YYCCSEJFVHRTKT-UHFFFAOYSA-N 4-[8-[2-(oxan-4-yl)ethyl]-6-oxo-5,7-dihydropyrazino[2,3-b]pyrazin-2-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C(NC(=O)CN2CCC3CCOCC3)C2=N1 YYCCSEJFVHRTKT-UHFFFAOYSA-N 0.000 description 1
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
• GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
• NXFSUXQVMKGXDK-UHFFFAOYSA-N 4-methyl-5-[5-(oxan-4-ylmethyl)-6-oxo-7,8-dihydropyrazino[2,3-b]pyrazin-3-yl]pyridine-2-carboxamide Chemical compound CC1=CC(C(N)=O)=NC=C1C1=CN=C(NCC(=O)N2CC3CCOCC3)C2=N1 NXFSUXQVMKGXDK-UHFFFAOYSA-N 0.000 description 1
• DQWKXJYJKDPLMT-UHFFFAOYSA-N 5-phenoxy-1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical compound N1=C2NC(=O)NC2=CC=C1OC1=CC=CC=C1 DQWKXJYJKDPLMT-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• SEBCRFUXBLJQHQ-UHFFFAOYSA-N 9-(2-hydroxyethyl)-2-methylpurine-6-carboxamide Chemical compound CC1=NC(C(N)=O)=C2N=CN(CCO)C2=N1 SEBCRFUXBLJQHQ-UHFFFAOYSA-N 0.000 description 1
• MWKDGWKQVQCNGG-UHFFFAOYSA-N 9-(2-hydroxyethyl)-2-phenylpurine-6-carboxamide Chemical compound N=1C=2N(CCO)C=NC=2C(C(=O)N)=NC=1C1=CC=CC=C1 MWKDGWKQVQCNGG-UHFFFAOYSA-N 0.000 description 1
• 244000215068 Acacia senegal Species 0.000 description 1
• 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
• 229920001817 Agar Polymers 0.000 description 1
• 108010082126 Alanine transaminase Proteins 0.000 description 1
• 239000005995 Aluminium silicate Substances 0.000 description 1
• 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
• 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
• 201000001320 Atherosclerosis Diseases 0.000 description 1
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
• COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
• JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
• 102000047934 Caspase-3/7 Human genes 0.000 description 1
• 108700037887 Caspase-3/7 Proteins 0.000 description 1
• 241000700199 Cavia porcellus Species 0.000 description 1
• 241000282693 Cercopithecidae Species 0.000 description 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
• 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
• 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
• 208000006154 Chronic hepatitis C Diseases 0.000 description 1
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
• 241000207199 Citrus Species 0.000 description 1
• 229920002261 Corn starch Polymers 0.000 description 1
• 108090000695 Cytokines Proteins 0.000 description 1
• 102000004127 Cytokines Human genes 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
• NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-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
• 206010012735 Diarrhoea Diseases 0.000 description 1
• 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
• 102000004190 Enzymes Human genes 0.000 description 1
• 108090000790 Enzymes Proteins 0.000 description 1
• 241000283073 Equus caballus Species 0.000 description 1
• 239000001856 Ethyl cellulose Substances 0.000 description 1
• ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• 241000287828 Gallus gallus Species 0.000 description 1
• 239000004471 Glycine Substances 0.000 description 1
• 229920002907 Guar gum Polymers 0.000 description 1
• 229920000084 Gum arabic Polymers 0.000 description 1
• 239000007995 HEPES buffer Substances 0.000 description 1
• 208000031886 HIV Infections Diseases 0.000 description 1
• 208000037357 HIV infectious disease Diseases 0.000 description 1
• 102000001554 Hemoglobins Human genes 0.000 description 1
• 108010054147 Hemoglobins Proteins 0.000 description 1
• 206010019695 Hepatic neoplasm Diseases 0.000 description 1
• 208000005176 Hepatitis C Diseases 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
• 206010061218 Inflammation Diseases 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
• 240000007472 Leucaena leucocephala Species 0.000 description 1
• 235000010643 Leucaena leucocephala Nutrition 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
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
• 206010025476 Malabsorption Diseases 0.000 description 1
• 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• 206010027476 Metastases Diseases 0.000 description 1
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
• 241000699660 Mus musculus Species 0.000 description 1
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
• BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 1
• 150000007945 N-acyl ureas Chemical class 0.000 description 1
• 208000008589 Obesity Diseases 0.000 description 1
• 102000043276 Oncogene Human genes 0.000 description 1
• 108700020796 Oncogene Proteins 0.000 description 1
• 241000283973 Oryctolagus cuniculus Species 0.000 description 1
• 208000002193 Pain Diseases 0.000 description 1
• 206010033645 Pancreatitis Diseases 0.000 description 1
• 206010033647 Pancreatitis acute Diseases 0.000 description 1
• 206010033649 Pancreatitis chronic Diseases 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 241000009328 Perro Species 0.000 description 1
• 241000286209 Phasianidae Species 0.000 description 1
• 239000004743 Polypropylene Substances 0.000 description 1
• 229920001213 Polysorbate 20 Polymers 0.000 description 1
• 102000052575 Proto-Oncogene Human genes 0.000 description 1
• 108700020978 Proto-Oncogene Proteins 0.000 description 1
• 241000700159 Rattus Species 0.000 description 1
• 108091006629 SLC13A2 Proteins 0.000 description 1
• 208000003837 Second Primary Neoplasms Diseases 0.000 description 1
• 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 1
• 208000000453 Skin Neoplasms Diseases 0.000 description 1
• 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 1
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
• 241000282898 Sus scrofa Species 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
• 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
• 206010052779 Transplant rejections Diseases 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
• 239000013504 Triton X-100 Substances 0.000 description 1
• 229920004890 Triton X-100 Polymers 0.000 description 1
• 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
• 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
• 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
• 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
• 229940127538 Vascular Endothelial Growth Factor Receptor Inhibitors Drugs 0.000 description 1
• 208000036142 Viral infection Diseases 0.000 description 1
• 241000700605 Viruses Species 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
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• JEIVYJHYJKISIY-UHFFFAOYSA-N [2-(benzoyloxymethyl)-3-(6-carbamoyl-2-methylpurin-9-yl)cyclobutyl]methyl benzoate Chemical compound C12=NC(C)=NC(C(N)=O)=C2N=CN1C(C1COC(=O)C=2C=CC=CC=2)CC1COC(=O)C1=CC=CC=C1 JEIVYJHYJKISIY-UHFFFAOYSA-N 0.000 description 1
• 235000010489 acacia gum Nutrition 0.000 description 1
• 239000000205 acacia gum Substances 0.000 description 1
• 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
• 230000004913 activation Effects 0.000 description 1
• 239000008186 active pharmaceutical agent Substances 0.000 description 1
• 230000001154 acute effect Effects 0.000 description 1
• 201000003229 acute pancreatitis Diseases 0.000 description 1
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 230000002411 adverse Effects 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 239000000783 alginic acid Substances 0.000 description 1
• 229960001126 alginic acid Drugs 0.000 description 1
• 150000004781 alginic acids Chemical class 0.000 description 1
• 125000005907 alkyl ester group Chemical group 0.000 description 1
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• 235000012211 aluminium silicate Nutrition 0.000 description 1
• CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
• 229940063655 aluminum stearate Drugs 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
• 230000001093 anti-cancer Effects 0.000 description 1
• 238000003782 apoptosis assay Methods 0.000 description 1
• 230000006907 apoptotic process Effects 0.000 description 1
• 230000005735 apoptotic response Effects 0.000 description 1
• 235000015197 apple juice Nutrition 0.000 description 1
• 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
• 230000001174 ascending effect Effects 0.000 description 1
• 238000003149 assay kit Methods 0.000 description 1
• 125000002393 azetidinyl group Chemical group 0.000 description 1
• 125000004069 aziridinyl group Chemical group 0.000 description 1
• 230000009286 beneficial effect Effects 0.000 description 1
• 239000000440 bentonite Substances 0.000 description 1
• 229910000278 bentonite Inorganic materials 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
• JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
• 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
• 125000002619 bicyclic group Chemical group 0.000 description 1
• 238000010256 biochemical assay Methods 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 210000004369 blood Anatomy 0.000 description 1
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
• 229910052794 bromium Inorganic materials 0.000 description 1
• 239000007853 buffer solution Substances 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• 229910000019 calcium carbonate Inorganic materials 0.000 description 1
• 235000010216 calcium carbonate Nutrition 0.000 description 1
• FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
• 239000001354 calcium citrate Substances 0.000 description 1
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
• 235000013539 calcium stearate Nutrition 0.000 description 1
• 239000008116 calcium stearate Substances 0.000 description 1
• OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
• 238000004364 calculation method Methods 0.000 description 1
• 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
• 125000002837 carbocyclic group Chemical group 0.000 description 1
• 150000001721 carbon Chemical group 0.000 description 1
• 229910052799 carbon Inorganic materials 0.000 description 1
• 150000001722 carbon compounds Chemical class 0.000 description 1
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
• 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 239000003729 cation exchange resin Substances 0.000 description 1
• 229940023913 cation exchange resins Drugs 0.000 description 1
• 230000021164 cell adhesion Effects 0.000 description 1
• 238000000423 cell based assay Methods 0.000 description 1
• 230000006369 cell cycle progression Effects 0.000 description 1
• 230000024245 cell differentiation Effects 0.000 description 1
• 230000003915 cell function Effects 0.000 description 1
• 230000010261 cell growth Effects 0.000 description 1
• 230000003833 cell viability Effects 0.000 description 1
• 210000003169 central nervous system Anatomy 0.000 description 1
• 235000013339 cereals Nutrition 0.000 description 1
• 210000003679 cervix uteri Anatomy 0.000 description 1
• 230000002113 chemopreventative effect Effects 0.000 description 1
• 238000002512 chemotherapy Methods 0.000 description 1
• 239000000460 chlorine Substances 0.000 description 1
• 229910052801 chlorine Inorganic materials 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
• 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
• 208000037976 chronic inflammation Diseases 0.000 description 1
• 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
• 235000020971 citrus fruits Nutrition 0.000 description 1
• 238000012790 confirmation Methods 0.000 description 1
• 239000007799 cork Substances 0.000 description 1
• 235000005822 corn Nutrition 0.000 description 1
• 229940109239 creatinine Drugs 0.000 description 1
• 108010073357 cyanoginosin LR Proteins 0.000 description 1
• WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
• 125000006165 cyclic alkyl group Chemical group 0.000 description 1
• 125000004367 cycloalkylaryl group Chemical group 0.000 description 1
• 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
• 230000002380 cytological effect Effects 0.000 description 1
• 230000002074 deregulated effect Effects 0.000 description 1
• 239000000032 diagnostic agent Substances 0.000 description 1
• 229940039227 diagnostic agent Drugs 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
• 125000005433 dihydrobenzodioxinyl group Chemical group O1C(COC2=C1C=CC=C2)* 0.000 description 1
• 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
• 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
• 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• 238000007907 direct compression Methods 0.000 description 1
• 239000002270 dispersing agent Substances 0.000 description 1
• 125000005883 dithianyl group Chemical group 0.000 description 1
• 238000007876 drug discovery Methods 0.000 description 1
• 239000003596 drug target Substances 0.000 description 1
• 238000007908 dry granulation Methods 0.000 description 1
• 230000009977 dual effect Effects 0.000 description 1
• 210000005069 ears Anatomy 0.000 description 1
• 230000005014 ectopic expression Effects 0.000 description 1
• 235000019325 ethyl cellulose Nutrition 0.000 description 1
• 229920001249 ethyl cellulose Polymers 0.000 description 1
• 229940012017 ethylenediamine Drugs 0.000 description 1
• 230000005284 excitation Effects 0.000 description 1
• 238000002474 experimental method Methods 0.000 description 1
• 235000019634 flavors Nutrition 0.000 description 1
• 235000013312 flour Nutrition 0.000 description 1
• 238000002376 fluorescence recovery after photobleaching Methods 0.000 description 1
• 235000013355 food flavoring agent Nutrition 0.000 description 1
• 230000037406 food intake Effects 0.000 description 1
• 235000012631 food intake Nutrition 0.000 description 1
• 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 239000007903 gelatin capsule Substances 0.000 description 1
• 235000001727 glucose Nutrition 0.000 description 1
• 239000008187 granular material Substances 0.000 description 1
• 239000003102 growth factor Substances 0.000 description 1
• 235000010417 guar gum Nutrition 0.000 description 1
• 239000000665 guar gum Substances 0.000 description 1
• 229960002154 guar gum Drugs 0.000 description 1
• 235000015220 hamburgers Nutrition 0.000 description 1
• 208000019622 heart disease Diseases 0.000 description 1
• 230000004217 heart function Effects 0.000 description 1
• 208000002672 hepatitis B Diseases 0.000 description 1
• 208000010710 hepatitis C virus infection Diseases 0.000 description 1
• 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
• 231100000171 higher toxicity Toxicity 0.000 description 1
• 238000001794 hormone therapy Methods 0.000 description 1
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
• 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
• QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 1
• 239000001341 hydroxy propyl starch Substances 0.000 description 1
• 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
• 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
• 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
• 239000012216 imaging agent Substances 0.000 description 1
• JXXWJMUPNZDILL-UHFFFAOYSA-N imidazo[4,5-b]pyridin-2-one Chemical compound C1=CC=NC2=NC(=O)N=C21 JXXWJMUPNZDILL-UHFFFAOYSA-N 0.000 description 1
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
• 238000000338 in vitro Methods 0.000 description 1
• 238000001727 in vivo Methods 0.000 description 1
• 238000005462 in vivo assay Methods 0.000 description 1
• 238000011503 in vivo imaging Methods 0.000 description 1
• 208000019016 inability to swallow Diseases 0.000 description 1
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
• 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
• 230000006698 induction Effects 0.000 description 1
• 230000006882 induction of apoptosis Effects 0.000 description 1
• 208000027866 inflammatory disease Diseases 0.000 description 1
• 230000004054 inflammatory process Effects 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• 230000003993 interaction Effects 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 229940044173 iodine-125 Drugs 0.000 description 1
• 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
• 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
• 125000001786 isothiazolyl group Chemical group 0.000 description 1
• NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 208000014018 liver neoplasm Diseases 0.000 description 1
• 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
• 210000003141 lower extremity Anatomy 0.000 description 1
• 208000020816 lung neoplasm Diseases 0.000 description 1
• 208000037841 lung tumor Diseases 0.000 description 1
• 229940124302 mTOR inhibitor Drugs 0.000 description 1
• 208000002780 macular degeneration Diseases 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 238000012423 maintenance Methods 0.000 description 1
• 230000007257 malfunction Effects 0.000 description 1
• 230000036210 malignancy Effects 0.000 description 1
• 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
• 239000000463 material Substances 0.000 description 1
• 235000012054 meals Nutrition 0.000 description 1
• 238000005259 measurement Methods 0.000 description 1
• 230000007246 mechanism Effects 0.000 description 1
• 229960003194 meglumine Drugs 0.000 description 1
• 238000002844 melting Methods 0.000 description 1
• 230000008018 melting Effects 0.000 description 1
• 229940041616 menthol Drugs 0.000 description 1
• 239000002207 metabolite Substances 0.000 description 1
• 230000001394 metastastic effect Effects 0.000 description 1
• FQJZWXRBDFNVOX-UHFFFAOYSA-N methyl 4-[3-(cyclohexylmethyl)-2-oxo-1h-imidazo[4,5-b]pyrazin-5-yl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C1=CN=C(NC(=O)N2CC3CCCCC3)C2=N1 FQJZWXRBDFNVOX-UHFFFAOYSA-N 0.000 description 1
• 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
• 229960002216 methylparaben Drugs 0.000 description 1
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
• 239000003094 microcapsule Substances 0.000 description 1
• 229940016286 microcrystalline cellulose Drugs 0.000 description 1
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
• 239000008108 microcrystalline cellulose Substances 0.000 description 1
• ZYZCGGRZINLQBL-GWRQVWKTSA-N microcystin-LR Chemical compound C([C@H](OC)[C@@H](C)\C=C(/C)\C=C\[C@H]1[C@@H](C(=O)N[C@H](CCC(=O)N(C)C(=C)C(=O)N[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]([C@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(O)=O)C(O)=O)C)C1=CC=CC=C1 ZYZCGGRZINLQBL-GWRQVWKTSA-N 0.000 description 1
• DIDLWIPCWUSYPF-UHFFFAOYSA-N microcystin-LR Natural products COC(Cc1ccccc1)C(C)C=C(/C)C=CC2NC(=O)C(NC(CCCNC(=N)N)C(=O)O)NC(=O)C(C)C(NC(=O)C(NC(CC(C)C)C(=O)O)NC(=O)C(C)NC(=O)C(=C)N(C)C(=O)CCC(NC(=O)C2C)C(=O)O)C(=O)O DIDLWIPCWUSYPF-UHFFFAOYSA-N 0.000 description 1
• 238000002156 mixing Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• VHCVFIPXRYKNHG-UHFFFAOYSA-N n-[3-[2-oxo-3-(1-phenylethyl)-1h-imidazo[4,5-b]pyrazin-5-yl]phenyl]methanesulfonamide Chemical compound C12=NC(C=3C=C(NS(C)(=O)=O)C=CC=3)=CN=C2NC(=O)N1C(C)C1=CC=CC=C1 VHCVFIPXRYKNHG-UHFFFAOYSA-N 0.000 description 1
• HDJQSVHBEAPTEU-UHFFFAOYSA-N n-[4-[2-oxo-3-(1-phenylethyl)-1h-imidazo[4,5-b]pyrazin-5-yl]phenyl]methanesulfonamide Chemical compound C12=NC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CN=C2NC(=O)N1C(C)C1=CC=CC=C1 HDJQSVHBEAPTEU-UHFFFAOYSA-N 0.000 description 1
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
• 230000001613 neoplastic effect Effects 0.000 description 1
• 201000011519 neuroendocrine tumor Diseases 0.000 description 1
• 210000000440 neutrophil Anatomy 0.000 description 1
• 238000011580 nude mouse model Methods 0.000 description 1
• 235000020824 obesity Nutrition 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
• 231100000590 oncogenic Toxicity 0.000 description 1
• 230000002246 oncogenic effect Effects 0.000 description 1
• 230000003287 optical effect Effects 0.000 description 1
• 235000015205 orange juice Nutrition 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• 150000007530 organic bases Chemical class 0.000 description 1
• 125000001715 oxadiazolyl group Chemical group 0.000 description 1
• IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 description 1
• 150000002921 oxetanes Chemical class 0.000 description 1
• 239000003182 parenteral nutrition solution Substances 0.000 description 1
• 208000033808 peripheral neuropathy Diseases 0.000 description 1
• 230000002085 persistent effect Effects 0.000 description 1
• 235000019271 petrolatum Nutrition 0.000 description 1
• 239000008177 pharmaceutical agent Substances 0.000 description 1
• WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
• 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
• 239000006187 pill Substances 0.000 description 1
• 238000011518 platinum-based chemotherapy Methods 0.000 description 1
• 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
• 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
• 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
• 229920001155 polypropylene Polymers 0.000 description 1
• 229920000136 polysorbate Polymers 0.000 description 1
• 229920000053 polysorbate 80 Polymers 0.000 description 1
• 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
• 239000013641 positive control Substances 0.000 description 1
• 229920001592 potato starch Polymers 0.000 description 1
• 229920003124 powdered cellulose Polymers 0.000 description 1
• 235000019814 powdered cellulose Nutrition 0.000 description 1
• 230000035935 pregnancy Effects 0.000 description 1
• 238000009597 pregnancy test Methods 0.000 description 1
• 239000003755 preservative agent Substances 0.000 description 1
• 230000002335 preservative 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
• 238000004393 prognosis Methods 0.000 description 1
• 230000000750 progressive effect Effects 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
• 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
• 229960003415 propylparaben Drugs 0.000 description 1
• 239000003223 protective agent Substances 0.000 description 1
• 238000000159 protein binding assay Methods 0.000 description 1
• 208000020016 psychiatric disease Diseases 0.000 description 1
• 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
• DDSCCYSKFCZQMP-UHFFFAOYSA-N purine-6-caboxamide Chemical compound NC(=O)C1=NC=NC2=C1N=CN2 DDSCCYSKFCZQMP-UHFFFAOYSA-N 0.000 description 1
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
• 150000003217 pyrazoles Chemical class 0.000 description 1
• 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
• 125000002755 pyrazolinyl group Chemical group 0.000 description 1
• ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
• 125000001422 pyrrolinyl group Chemical group 0.000 description 1
• 230000008707 rearrangement Effects 0.000 description 1
• 230000002829 reductive effect Effects 0.000 description 1
• 230000022983 regulation of cell cycle Effects 0.000 description 1
• 230000016515 regulation of signal transduction Effects 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 230000001850 reproductive effect Effects 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 238000012552 review Methods 0.000 description 1
• 229910052703 rhodium Inorganic materials 0.000 description 1
• 231100000279 safety data Toxicity 0.000 description 1
• 239000000565 sealant Substances 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 238000013207 serial dilution Methods 0.000 description 1
• 230000019491 signal transduction Effects 0.000 description 1
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 201000000849 skin cancer Diseases 0.000 description 1
• 201000006000 skin carcinoma in situ Diseases 0.000 description 1
• 239000011734 sodium Substances 0.000 description 1
• 229910052708 sodium Inorganic materials 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
• 235000010234 sodium benzoate Nutrition 0.000 description 1
• 239000004299 sodium benzoate Substances 0.000 description 1
• 229960003885 sodium benzoate Drugs 0.000 description 1
• 229940001607 sodium bisulfite Drugs 0.000 description 1
• 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
• 239000001509 sodium citrate Substances 0.000 description 1
• NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
• 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
• 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 235000010356 sorbitol Nutrition 0.000 description 1
• 241000894007 species Species 0.000 description 1
• GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• 238000007619 statistical method Methods 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 239000011550 stock solution Substances 0.000 description 1
• 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 239000013589 supplement Substances 0.000 description 1
• 239000000375 suspending agent Substances 0.000 description 1
• 238000010189 synthetic method Methods 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 230000009885 systemic effect Effects 0.000 description 1
• 239000007916 tablet composition Substances 0.000 description 1
• 230000008685 targeting Effects 0.000 description 1
• 235000002906 tartaric acid Nutrition 0.000 description 1
• 239000011975 tartaric acid Substances 0.000 description 1
• 238000003419 tautomerization reaction Methods 0.000 description 1
• 125000005944 tetrahydroimidazopyridyl group Chemical group 0.000 description 1
• 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
• 230000001225 therapeutic effect Effects 0.000 description 1
• 125000001113 thiadiazolyl group Chemical group 0.000 description 1
• 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
• 125000001984 thiazolidinyl group Chemical group 0.000 description 1
• 125000002769 thiazolinyl group Chemical group 0.000 description 1
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
• 238000011200 topical administration Methods 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• 125000004306 triazinyl group Chemical group 0.000 description 1
• 235000013337 tricalcium citrate Nutrition 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• 229910052722 tritium Inorganic materials 0.000 description 1
• 210000002700 urine Anatomy 0.000 description 1
• 230000004218 vascular function Effects 0.000 description 1
• 231100000747 viability assay Toxicity 0.000 description 1
• 238000003026 viability measurement method Methods 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 230000009385 viral infection Effects 0.000 description 1
• 238000005550 wet granulation Methods 0.000 description 1
• 239000003871 white petrolatum Substances 0.000 description 1
• 239000002023 wood Substances 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1