WO2022182395A1 - Small molecule inhibitors of stat3 n-terminal domain and methods of use - Google Patents
Small molecule inhibitors of stat3 n-terminal domain and methods of use Download PDFInfo
- Publication number
- WO2022182395A1 WO2022182395A1 PCT/US2021/058936 US2021058936W WO2022182395A1 WO 2022182395 A1 WO2022182395 A1 WO 2022182395A1 US 2021058936 W US2021058936 W US 2021058936W WO 2022182395 A1 WO2022182395 A1 WO 2022182395A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stnd
- formula
- pharmaceutically acceptable
- group
- acceptable salt
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title abstract description 59
- 150000003384 small molecules Chemical class 0.000 title description 6
- 101100311214 Xenopus laevis stat3.1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 108010017324 STAT3 Transcription Factor Proteins 0.000 claims abstract description 107
- 201000010099 disease Diseases 0.000 claims abstract description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 43
- 230000000694 effects Effects 0.000 claims abstract description 37
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 102000004495 STAT3 Transcription Factor Human genes 0.000 claims abstract description 29
- 201000011510 cancer Diseases 0.000 claims abstract description 27
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 10
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 125000003342 alkenyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 208000035143 Bacterial infection Diseases 0.000 claims description 12
- 208000036142 Viral infection Diseases 0.000 claims description 12
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 12
- 230000009385 viral infection Effects 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 208000027866 inflammatory disease Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 3
- 229940121649 protein inhibitor Drugs 0.000 claims 10
- 239000012268 protein inhibitor Substances 0.000 claims 10
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 77
- 125000004432 carbon atom Chemical group C* 0.000 description 48
- 210000004027 cell Anatomy 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 37
- -1 small molecule compounds Chemical class 0.000 description 36
- 239000000203 mixture Substances 0.000 description 22
- 238000009472 formulation Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 241000124008 Mammalia Species 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 7
- 102000003814 Interleukin-10 Human genes 0.000 description 7
- 108090000174 Interleukin-10 Proteins 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 239000003242 anti bacterial agent Substances 0.000 description 7
- 239000003443 antiviral agent Substances 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000002260 anti-inflammatory agent Substances 0.000 description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 239000003599 detergent Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 5
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229960005419 nitrogen Drugs 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 241000711573 Coronaviridae Species 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 150000002081 enamines Chemical class 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000001768 microscale thermophoresis Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241001678559 COVID-19 virus Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- 101000574441 Mus musculus Alkaline phosphatase, germ cell type Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001413 cellular effect Effects 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
- 239000013078 crystal Substances 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 150000002334 glycols Chemical class 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 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 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 208000011380 COVID-19–associated multisystem inflammatory syndrome in children Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 241000710803 Equine arteritis virus Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000005577 Gastroenteritis Diseases 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 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
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- 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 2
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 2
- 241000315672 SARS coronavirus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229960003022 amoxicillin Drugs 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003596 drug target Substances 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 210000005095 gastrointestinal system Anatomy 0.000 description 2
- 230000009395 genetic defect Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960005287 lincomycin Drugs 0.000 description 2
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 229940051866 mouthwash Drugs 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 2
- 229960002739 oxaprozin Drugs 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
- 239000008180 pharmaceutical surfactant Substances 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 102000003998 progesterone receptors Human genes 0.000 description 2
- 108090000468 progesterone receptors Proteins 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 210000000064 prostate epithelial cell Anatomy 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229960000311 ritonavir Drugs 0.000 description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229960001017 tolmetin Drugs 0.000 description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 125000006168 tricyclic group Chemical group 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- FIDLLEYNNRGVFR-CTNGQTDRSA-N (3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC1=C2N(C=CC1=O)N([C@@H]1COCCN1C2=O)[C@@H]1C2=C(SCC3=C1C=CC(F)=C3F)C=CC=C2 FIDLLEYNNRGVFR-CTNGQTDRSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-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
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 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
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010000890 Acute myelomonocytic leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 1
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004022 Bacterial food poisoning Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 1
- 229940124638 COX inhibitor Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241001466804 Carnivora Species 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229940122444 Chemokine receptor antagonist Drugs 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-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
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 101150111020 GLUL gene Proteins 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 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 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 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
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 241000588915 Klebsiella aerogenes Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 241000714216 Levivirus Species 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033835 Myelomonocytic Acute Leukemia Diseases 0.000 description 1
- 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 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 241001263478 Norovirus Species 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000283089 Perissodactyla Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 241001135989 Porcine reproductive and respiratory syndrome virus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000032236 Predisposition to disease Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 238000004617 QSAR study Methods 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241001147691 Staphylococcus saprophyticus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241001493546 Suina Species 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical class OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 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
- 229940123237 Taxane Drugs 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229950001573 abemaciclib Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 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
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 208000037831 acute erythroleukemic leukemia Diseases 0.000 description 1
- 208000037832 acute lymphoblastic B-cell leukemia Diseases 0.000 description 1
- 208000037833 acute lymphoblastic T-cell leukemia Diseases 0.000 description 1
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 208000011912 acute myelomonocytic leukemia M4 Diseases 0.000 description 1
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-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
- 229960000473 altretamine Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 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
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 201000007180 bile duct carcinoma Diseases 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast 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
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 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
- 229960004117 capecitabine Drugs 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 125000002579 carboxylato group Chemical group [O-]C(*)=O 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000002559 chemokine receptor antagonist Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 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
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-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
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960005338 clevudine Drugs 0.000 description 1
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 125000004982 dihaloalkyl group Chemical group 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- 229960002062 enfuvirtide Drugs 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 229940092559 enterobacter aerogenes Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 208000037828 epithelial carcinoma Diseases 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940125777 fusion inhibitor Drugs 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940075628 hypomethylating agent Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 208000037829 lymphangioendotheliosarcoma Diseases 0.000 description 1
- 208000012804 lymphangiosarcoma Diseases 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229940090008 naprosyn Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229960000801 nelarabine Drugs 0.000 description 1
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003865 nucleic acid synthesis inhibitor Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- JEECQCWWSTZDCK-IQZGDKDPSA-N omadacycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(CNCC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O JEECQCWWSTZDCK-IQZGDKDPSA-N 0.000 description 1
- 229950004150 omadacycline Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229960000471 pleconaril Drugs 0.000 description 1
- KQOXLKOJHVFTRN-UHFFFAOYSA-N pleconaril Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C KQOXLKOJHVFTRN-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002210 silicon-based material Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940030998 streptococcus agalactiae Drugs 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 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 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940006995 sulfamethoxazole and trimethoprim Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 1
- 229960005311 telbivudine Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- 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
- A61K31/12—Ketones
- A61K31/121—Ketones acyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
-
- 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
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4747—Quinolines; Isoquinolines spiro-condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- Signal transducer and activator of transcription 3 (STAT3) activity is a marker for many types of cancer and other diseases, such as diabetic nephropathy, skeletal muscle insulin resistance in type 2 diabetes, endometriosis, depression, asthma, colitis, renal fibrosis, inflammatory bowel disease, systemic lupus erythematosus (SLE), Alzheimer’s disease, Huntington’s disease, and autism.
- STAT3 Signal transducer and activator of transcription 3
- Inhibitors of the N-terminal domain of STAT3 produce different cellular and molecular effects compared to other known STAT3 inhibitors.
- inhibition of STAT3 N-terminal domain is considered a promising drug target for the treatment of cancer and infectious diseases.
- Peptide inhibitors of the domain have been demonstrated to induce immune responses to and clear Mycobacterium tuberculosis in mice and induce expression of proapoptotic genes in cancer cells.
- peptides can suffer from several drawbacks, including limited modes of administration, low selectivity, short life in circulation, and poor cell permeability.
- the invention provides a method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein comprising administering to a subject in need thereof a compound as described herein, particularly a phenol group-containing small molecule.
- STAT3 signal transducer and activator of transcription 3
- the small molecule compounds have been discovered to be inhibitors of STAT3 N-domain, thereby providing therapeutic treatments for a variety of diseases without specialized modes of administration.
- FIG. 1 is a reaction scheme of preparing STND-25.
- DIC is N.N' - diisopropylcarbodiimide.
- FIG. 2 is a reaction scheme of preparing STND-27.
- DIEA is N.N' - diisopropylethylamine.
- FIG. 3 is a reaction scheme of preparing STND-28.
- FIG. 4 is a reaction scheme of preparing STND-29.
- FIG. 5 is a reaction scheme of preparing STND-30.
- FIG. 6 is a reaction scheme of preparing STND-31.
- FIG. 7 is a reaction scheme of preparing STND-33.
- FIG. 8 is a reaction scheme of preparing STND-34.
- TMSC1 is chlorotrimethylsilane.
- FIG. 9 is a reaction scheme of preparing STND-37.
- FIG. 10 is a reaction scheme of preparing STND-38.
- FIG. 11 is a reaction scheme of preparing STND-39.
- FIG. 12 is a reaction scheme of preparing STND-40.
- FIG. 13 is a reaction scheme of preparing STND-42.
- FIG. 14 is a reaction scheme of preparing STND-43.
- FIG. 15 is a reaction scheme of preparing STND-44.
- FIG. 16 is a reaction scheme of preparing STND-45.
- FIG. 17 is a reaction scheme of preparing STND-46.
- FIG. 18 is a reaction scheme of preparing STND-47.
- FIG. 19 is bar graph of percent secreted embryonic alkaline phosphatase (SEAP) of compounds of aspects of the invention incubated with HEK-BLUE IL-10 reporter cells relative to a control set at 100%. From left to right, the bars represent STND-1 (black), STND-3 (stripe), STND-4 (white), STND-5 (black), STND-6 (stripe), STND-7 (white), STND-8 (black), STND-10 (stripe), STND-11 (white), STND-12 (black), STND-13 (stripe), STND-14 (white), STND-15 (black), STND-17 (stripe), STND-19 (white), STND-20 (black), and the control (last column).
- SEAP percent secreted embryonic alkaline phosphatase
- FIG. 20 is a graph showing the inhibition of IL-10 induced STAT3 signaling in HEK-BLUE IL-10 reporter cells versus concentration of STND-9.
- the data show the cell number, % from untreated ( ⁇ ) and IL-10-induced STAT3 activity, % of untreated (A).
- compounds exhibited cell toxicity ( ⁇ ).
- inhibition of STAT3 activity (A) was more significant and did not appear to be toxicity-mediated.
- FIG. 21 is a dose response curve of Fnorm (Fi/Fo) versus concentration of STND-9.
- FIG. 22 is graph of DU145 cell numbers after treatment versus concentration of inhibitor for the following compounds: ST3-H2A2 (positive control, STAT3 ND peptide inhibitor) ( ⁇ ), STND-2 ( ⁇ ), STND-8 (X), and STND-9 ( ⁇ ).
- ST3-H2A2 positive control, STAT3 ND peptide inhibitor
- STND-2 ⁇
- STND-8 X
- STND-9 ⁇
- FIG. 23 is a graph of DU145 cell (solid line) and normal prostate epithelial cells (RWPE-1) (dashed line) cell numbers after treatment versus concentration of inhibitor for the following compounds: STND-9 ( ⁇ ), STND-25 ( ⁇ ), and STND-34 ( ⁇ ).
- FIG. 24 is a graph of percent KPC95775 cells after treatment versus concentration of inhibitor for the following compounds: STND-9 ( ⁇ ), STND-25 ( ⁇ ), STND-30 (X), STND-31 (*), and STND-32 (A).
- the invention provides a method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein comprising administering to a subject in need thereof a phenol group-containing compound, a compound that is STND-3, STND-4, or STND-19, or a pharmaceutically acceptable salt thereof.
- STAT3 signal transducer and activator of transcription 3
- the phenol group-containing compound is a small molecule of formula (I) in which the remainder of the molecule is para to the OH group on the phenyl ring.
- the residue of the small molecule is bonded at the para position of the phenyl group through a carbon atom (e.g., that of an alkylene, an alkenyl, or a fused ring), a carbonyl, or an amino moiety.
- the phenol group-containing compound has a core structural residue selected from the group consisting of formula (la) wherein R 1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, provided that the compound of formula (la) is not formula (lb)
- each of the core structural residues of formulas (la) through (Ih) is bonded to the remainder of the phenol group-containing compound, or a compound or a pharmaceutically acceptable salt thereof that is selected from the group consisting of
- the core structural residue of formula (la) does not include the following compounds:
- R 1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido
- R 2 is selected from the group consisting of wherein
- R 3 is heterocyclyl
- R 4 is aryl, heteroaryl, or alkenyl
- R 5 is haloalkyl or alkenyl
- R 6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -SC alkenyl
- R 7 is H or alkyl
- R 8 is aryl or heteroaryl, each of which is optionally substituted, R 9 is alkyl or haloalkyl,
- X 3 is NH or O
- R 2 is selected from the group consisting of
- Exemplary compounds of formula (la-1) include , 5, , or a pharmaceutically acceptable salt thereof.
- the compound of formula (la-1) is STND-9
- STND-25, or STND-34 more preferably STND-25 or STND-34, or any pharmaceutically acceptable salt thereof.
- the phenol group-containing compound has a core structural residue of formula (lb) that forms formula (Ib-1)
- R 10 is selected from the group consisting of
- the phenol group-containing compound has a core structural residue of formula (Ic) that forms formula (Ic-1)
- the phenol group-containing compound has a core structural residue of formula (Id) that forms formula (Id-1)
- the phenol group-containing compound has a core structural residue of formula (Ie) that forms formula (Ie-1)
- X 1 is CH or N
- X 2 is a bond, CH2, or C(O),
- R 14 is H or F
- R 15 is selected from the group consisting of pharmaceutically acceptable salt thereof.
- Exemplary compounds of formula (Ie-1) include , -18, or a pharmaceutically acceptable salt thereof.
- the phenol group-containing compound has a core structural residue of formula (If) that forms formula (If-1)
- R 17 is H, alk l, R 18 is H or alkyl, n is an integer of 1-3, and R 19 is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
- Exemplary compounds of formula (If-1) include , or a pharmaceutically acceptable salt thereof.
- the phenol group-containing compound has a core structural residue of formula (Ig) that forms formula (Ig-1) (Ig-1), wherein
- R 21 is selected from the group consisting of pharmaceutically acceptable salt thereof.
- Exemplary compounds of formula (Ig-1) include or a pharmaceutically acceptable salt thereof.
- the phenol group-containing compound has a core structural residue of formula (Ih) that forms formula (Ih-1) (Ih-1), wherein R 22 is selected from the group consisting of -32, or a pharmaceutically acceptable salt thereof.
- the compound used in the method is selected from the group consisting of -19, or a pharmaceutically acceptable salt thereof.
- the present invention further provides exemplary compounds of formula (la-1) wherein
- R 1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido
- R 2 is selected from the group consisting of
- R 3 is heterocyclyl
- R 4 is aryl, heteroaryl, or alkenyl
- R 5 is haloalkyl or alkenyl
- R 6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl,
- R 7 is H or alkyl
- R 8 is aryl or heteroaryl, each of which is optionally substituted
- R 9 is alkyl or haloalkyl
- X 3 is NH or O
- X 4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof provided that the compound of formula (la-1) is not STND-5, STND-8, STND-9, STND-24, STND-25, STND-35, or STND-36, and in some aspects of the invention, the compound of formula (la-1) also is not STND-43, STND-44, or STND-45: , [0052] In some aspects of the invention, the genus of formula (la-1) does not include one or more of the following compounds:
- the compound of formula (la-1) preferably is -33, or a pharmaceutically acceptable salt thereof.
- the compound of formula (la-1) is STND-29, STND-33, STND-34, STND-37, STND-38, STND-39, STND-40, STND-41, STND-42,
- alkyl implies a straight-chain or branched alkyl substituent containing from, for example, from 1 to about 8 carbon atoms, e.g., from about 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms.
- alkyl group include methyl, ethyl, «-propyl, isopropyl, «-butyl, vec-butyl. isobutyl, tert-butyl, «-pentyl, isopentyl, «-hexyl, and the like.
- alkyl occurs as part of a group, such as, e.g., in C3-C6 cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl (-C(O)alkyl), alkylcarboxy (-C(O)Oalkyl), arylalkyl, heteroarylalkyl, etc.
- haloalkyl e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl
- cyanoalkyl aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkyl,
- the alkyl can be substituted or unsubstituted, as described herein. Even in instances in which the alkyl is an alkylene chain (e.g., -(CH2)n-), the alkyl group can be substituted or unsubstituted.
- the alkyl is an alkylene chain (e.g., -(CH2)n-)
- the alkyl group can be substituted or unsubstituted.
- alkenyl means a linear alkenyl substituent containing from, for example, 2 to about 8 carbon atoms (branched alkenyls are about 3 to about 8 carbons atoms), e.g., from 2 to about 6 carbon atoms (branch alkenyls are about 3 to about 6 carbon atoms), from about 3 to about 5 carbon atoms (branched alkenyls are about 3 to about 6 carbons atoms).
- the alkenyl group is a C2-C6 alkenyl or C2-C4 alkenyl.
- alkenyl group examples include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1- hexenyl, and the like.
- the alkenyl can be substituted or unsubstituted, as described herein.
- cycloalkyl means a cyclic alkyl moiety containing from, for example, 3 to about 6 carbon atoms or from 5 to about 6 carbon atoms. Examples of such moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- the cycloalkyl can be substituted or unsubstituted, as described herein.
- aryl refers to a mono, bi, or tricyclic carbocycbc ring system having one, two, or three aromatic rings, for example, phenyl, naphthyl, anthracenyl, or biphenyl.
- aryl refers to an unsubstituted or substituted aromatic carbocycbc moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like.
- heterocyclyl encompasses both heteroaryl groups and heterocycloalkyl groups, as described herein.
- heteroaryl refers to aromatic 5- or 6- membered monocyclic groups, 9- or 10-membered bicycbc groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings.
- Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
- the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
- the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quatemized.
- Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
- the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
- heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl (thiophenyl), isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl.
- the heteroaryl can be substituted or unsubstituted, as described herein.
- heterocycloalkyl means a stable, saturated, or partially unsaturated monocyclic, bicyclic, and spiro ring system containing 3 to 7 ring members of carbon atoms and other atoms selected from the group consisting of nitrogen, sulfur, and/or oxygen.
- a heterocycloalkyl is a 5-, 6-, or 7-membered monocyclic ring and contains one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
- the heterocycloalkyl may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure.
- heterocycloalkyl rings examples include isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl.
- the heterocycloalkyl can be substituted or unsubstituted, as described herein.
- the term “hydroxy” refers to the group -OH.
- cyano refers to the group -CN
- thiocyano refers to -SCN
- alkoxy and cycloalkyloxy embrace linear or branched alkyl and cycloalkyl groups, respectively, that are attached to a divalent oxygen.
- the alkyl and cycloalkyl groups are the same as described herein.
- halo refers to a halogen selected from fluorine, chlorine, bromine, and iodine.
- the term “carboxylato” refers to the group -C(0)OH.
- the term “amino” refers to the group -NH2.
- alkylamino refers to -NHR, whereas the term “dialkylamino” refers to -NRR'.
- R and R' are the same or different and each is a substituted or unsubstituted alkyl group, as described herein.
- the term “amido” refers to the group -C(0)NRR', which R and R' are the same or different and each is hydrogen or a substituted or unsubstituted alkyl group, as described herein.
- any substituent that is not hydrogen can be an optionally substituted moiety.
- the substituted moiety typically comprises at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position (e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.).
- aryl group When an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy, and others, the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g.,
- substituents for any non-hydrogen substituent include, e.g., halo, alkyl, alkenyl, hydroxy, nitro, cyano, thiocyano, amino, alkylamino, alkoxy, aryloxy, aralkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido, haloalkylamido, aryl, heteroaryl, and heterocycloalkyl, each of which is described herein.
- the substituent is at least one (e.g., 1 or 2) alkyl, halo, and/or haloalkyl.
- any of the aspects above whenever a range of the number of atoms in a structure is indicated (e.g., a Ci-12, Ci-8, Ci-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., Ci-Cx).
- 1- 6 carbon atoms e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, and/or 8 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3
- n represents the number of methylene repeat units in formula (If).
- n is an integer of either 1, 2, or 3.
- the subscript “m” represents the number of methylene repeat units in formula (Ia- 1).
- the subscript m is an integer from 1-5 (i.e., 1, 2, 3, 4, or 5).
- salts or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
- an inorganic acid e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid
- an organic acid e.g., formic acid, oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid
- an inorganic base e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide
- an organic base e.g., methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine
- an amino acid e.g., lysine, arginine, or alanine
- nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical.
- suitable salts are found in Remington ’s Pharmaceutical Sciences , 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).
- they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.
- co-administered or “co-administration” used herein refer to simultaneous or sequential administration.
- the Enamine library of in-stock compounds containing almost 2 million entries was used for initial screens that evaluated the binding pockets and identified early hits (e.g., STND-1 through STND-7). Additional hits came from screening larger Enamine diversity libraries containing 5 and 15 million compounds (e.g., STND-15 through STND-18). The highest scoring hits have been used for identification of potential binders in similarity searches. Search engine GIGA (www.molsoft.com/giga-search.html) was used for screening of the REAL database of 1.2 billion synthesizable compounds from Enamine (enamine.net/bbrary-synthesis/real-compounds/real-database).
- Quantitative Neighborhoods of Atoms (QNA) methodology was used for screening SAVI (Synthetically Accessible Virtual Inventory).
- SAVI has been recently generated using CHMTRN (CHeMistry TRaNslator) adaptation for a knowledge-based forward synthesis computer program (Judson et al., J Chem Inf Model, 2020, 60(1), 3336-3341).
- CHMTRN CHeMistry TRaNslator
- the latest version of SAVI used in the screens contains 1.75 billion entries and first became publicly available November 11, 2020 (Patel et al., Scientific Data, November 11, 2020, 7(384), 1-14).
- a pharmaceutical composition comprises at least one STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable excipients described herein for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available.
- the pharmaceutically acceptable carrier is one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.
- the pharmaceutical compositions can be administered as oral, sublingual, transdermal, subcutaneous, topical, absorption through epithelial or mucocutaneous linings, intravenous, intranasal, intraarterial, intraperitoneal, intramuscular, intratumoral, peritumoral, intraperitoneal, intrathecal, rectal, vaginal, or aerosol formulations.
- the pharmaceutical composition is administered orally or intravenously.
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered orally to a subject in need thereof.
- Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice and include an additive, such as cyclodextrin (e.g., a-, b-, or g-cyclodextrin, hydroxypropyl cyclodextrin) or polyethylene glycol (e.g., PEG400); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions and gels.
- diluents such as water, saline
- Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
- diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
- Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
- Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
- Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
- a flavor usually sucrose and acacia or tragacanth
- pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
- Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a salt thereof can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2, 2-dimethyl- 1,3- dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers
- Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
- Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
- suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
- the parenteral formulations typically contain from about 0.5 to about 25% by weight of the inhibitors in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
- HLB hydrophile-lipophile balance
- parenteral formulations can be presented in unit-dose or multi dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
- sterile liquid carrier for example, water
- Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
- the inhibitors can be made into injectable formulations.
- the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, ⁇ . B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).
- Topically applied compositions are generally in the form of liquids (e.g., mouthwash), creams, pastes, lotions, gels, and transdermal patches.
- Topical administration includes application to the skin and oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa.
- the composition contains at least one active component and a suitable vehicle or carrier. It can also contain other components, such as an anti-irritant.
- the carrier can be a liquid, solid or semi-solid.
- the composition is an aqueous solution, such as a mouthwash.
- the composition can be a dispersion, emulsion, gel, lotion, or cream vehicle for the various components.
- the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral.
- the liquid vehicle can include other materials, such as buffers, alcohols, glycols, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site.
- the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin, and silicone based materials.
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.
- aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
- the dose administered to the subject, particularly human and other mammals, in accordance with the present invention should be sufficient to affect the desired response.
- dosage will depend upon a variety of factors, including the age, condition or disease state, predisposition to disease, genetic defect or defects, and body weight of the mammal.
- the size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular inhibitor and the desired effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.
- inventive methods comprise administering an effective amount of a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof.
- An “effective amount” means an amount sufficient to show a meaningful benefit in an individual, cell, or tissue to be treated.
- a meaningful benefit includes, for example, detectably treating, relieving, healing, preventing, delaying the onset of, ameliorating, or lessening one or more symptoms of a disease mediated by overexpression of STAT3 (e.g., inflammation, fluid accumulation), inhibiting, arresting development, preventing, or halting further development of a viral infection or disease, promoting at least one aspect of tumor cell cytotoxicity (e.g., inhibition of growth, inhibiting survival of a cancer cell, reducing proliferation, reducing size and/or mass of a tumor (e.g., solid tumor)).
- the meaningful benefit observed in the subject can be to any suitable degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more or anything in between each of these percentages).
- one or more symptoms of the disease are treated, prevented, reduced, halted, or eliminated subsequent to administration of a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, thereby effectively treating the disease (e.g., disease caused by a bacterium or virus, cancer) to at least some degree.
- a STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, thereby effectively treating the disease (e.g., disease caused by a bacterium or virus, cancer) to at least some degree.
- Effective amounts can vary depending upon the biological effect desired in the individual, condition to be treated, and/or the specific characteristics of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, and the individual.
- any suitable dose of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered to the subject (e.g., human), according to the type of disease (e.g., disease caused by a bacterium or virus, cancer) to be treated.
- the dose of the STAT3 inhibitor compound desirably comprises about 0.01 mg per kilogram (kg) of the body weight of the subject (mg/kg) or more (e.g., about 0.05 mg/kg or more, 0.1 mg/kg or more, 0.5 mg/kg or more, 1 mg/kg or more, 2 mg/kg or more, 5 mg/kg or more, 10 mg/kg or more, 15 mg/kg or more, 20 mg/kg or more, 30 mg/kg or more, 40 mg/kg or more, 50 mg/kg or more, 75 mg/kg or more, 100 mg/kg or more, 125 mg/kg or more, 150 mg/kg or more, 175 mg/kg or more, 200 mg/kg or more, 225 mg/kg or more, 250 mg/kg or more, 275 mg/kg or more, 300 mg/kg or more, 325 mg/kg or more, 350 mg/kg or more, 375 mg
- the dose will be about 500 mg/kg or less (e.g., about 475 mg/kg or less, about 450 mg/kg or less, about 425 mg/kg or less, about 400 mg/kg or less, about 375 mg/kg or less, about 350 mg/kg or less, about 325 mg/kg or less, about 300 mg/kg or less, about 275 mg/kg or less, about 250 mg/kg or less, about 225 mg/kg or less, about 200 mg/kg or less, about 175 mg/kg or less, about 150 mg/kg or less, about 125 mg/kg or less, about 100 mg/kg or less, about 75 mg/kg or less, about 50 mg/kg or less, about 40 mg/kg or less, about 30 mg/kg or less, about 20 mg/kg or less, about 15 mg/kg or less, about 10 mg/kg or less, about 5 mg/kg or less, about 2 mg/kg or less, about 1 mg/kg or less, about 0.5 mg/kg or less, or about 0.1 mg/kg or less, about
- the term “subject” preferably is directed to a mammal.
- Mammals include, but are not limited to, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perissodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Cebids, or Simioids (monkeys) or of the order Anthropoids (humans and apes).
- STAT3 has been long considered a promising drug target due to its involvement in proliferation of tumor cells, inflammation, and immune responses. See, e.g., Bharadwaj et al., Pharmacol Rev 2020, 72 (2), 486-526; Huynh et al., Nat Rev Cancer 2019, 19 (2), 82-96; Gkouveris et al., Journal of Cancer Therapy , 2015, 6, 709-726; WO 2012/159107, and WO 2010/062681. An aberrant STAT3 pathway has also been shown to play a critical role in the pathogenesis of SARS-CoV-2 (Matsuyama et al., Cell Death Differ, October 9, 2020,
- N-terminal domain of STAT3 has emerged as a very different target (Hu et al ,Mol Cell Biol, 2015, 35(19), 3284-300) and inhibitors of the domain produce significantly different cellular and molecular effects compared to other STAT3 inhibitors (Timofeeva et al., ACS Chem Biol, 2007, 2(12), 799-809; and Timofeeva et al., Proc Natl Acad Sci USA, 2013, 110(A), 1267-1272).
- a functional aspect is that inhibitors of STAT3 N-domain impact not only tumor cells proliferation, but also immune responses to tumors and bacterial and viral pathogens.
- a STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), inhibits and/or reduces STAT3 activity, preferably STAT3 N-domain activity, in a cell, such as a cancer cell.
- the method includes contacting a cell with a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, whereby the activity of STAT3, particularly STAT3 N-domain, in the cell is inhibited.
- the STAT3 activity can be measured by any method, including the assays described herein.
- STAT3 has been described in the art as a viable treatment of diseases that are characterized as overexpressing STAT3.
- peptide STAT3 N-domain inhibitors have been shown to up-regulate expression of several proapoptotic proteins, in particular c-Fos (Timofeeva et al., Proc Natl Acad Sci USA, 2013, 110 (4), 1267-1272).
- Western blot analysis of c-Fos expression has shown that the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), effectively increase c-Fos expression in prostate cancer cells.
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), can be administered to a subject in need thereof as part of a treatment method for diseases that overexpress STAT3 (e.g., a disease caused by a bacterium or virus, cancer).
- diseases that overexpress STAT3 e.g., a disease caused by a bacterium or virus, cancer.
- the disease associated with increased activity of STAT3 protein can be, for example, a bacterial infection, a viral infection, an inflammatory disease, or cancer.
- the disease can be a bacterial infection (including a disease caused by a bacterial infection) or a viral infection (including a disease caused by a viral infection).
- the bacterial infection can be caused by, for example, Staphylococcus aureus, gram positive methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus saprophyticus, Pseudomonas aeruginosa, Listeria monocytogenes, Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Haemophilus influenzae, Helicobacter pylori, Salmonella, Shigella, Clostridium, Enterobacter aerogenes, gram negative Escherichia coli, Clostridium difficile, or a combination thereof.
- Diseases caused by a bacterial infection include, e.g., tuberculosis, gastritis, meningitis, gonorrhea, pneumonia, bacterial food poisoning, strep throat, cellulitis, wound infections, and toxic shock syndrome.
- the bacterial infection is tuberculosis.
- the viral infection can be, e.g., influenza virus (e.g., H1N1, H1N2, and H5N1), gastroenteritis, hepatitis virus, herpes simplex virus, West Nile virus, Ebola, human papillomavirus, coronavirus, chickenpox virus, flavivirus, togavirus, levivirus, norovirus, rotavirus, adenovirus, parvovirus, poliovirus, or a combination thereof.
- the coronavirus can be, for example, SARS-CoV, SARS-CoV-2, or MERS-CoV.
- the disease associated with increased activity of STAT3 protein is SARS-CoV-2.
- Diseases caused by a viral infection include, e.g., coronavirus disease (COVID-19), severe acute respiratory syndrome (SARS) virus, Middle East respiratory syndrome (MERS), a respiratory disease (e.g., pneumonia, bronchitis, pleural effusion), an inflammatory disease (e.g., inflammation, COVID-19-induced inflammation, pediatric multi-system inflammatory syndrome (PMIS)), reproductive and respiratory syndrome virus (PRRSV), equine arteritis virus (EAV), or gastroenteritis.
- coronavirus disease COVID-19
- SARS severe acute respiratory syndrome
- MERS Middle East respiratory syndrome
- a respiratory disease e.g., pneumonia, bronchitis, pleural effusion
- an inflammatory disease e.g., inflammation, COVID-19-induced inflammation, pediatric multi-system inflammatory syndrome (PMIS)
- PRRSV reproductive and respiratory syndrome virus
- EAV equine arteritis virus
- the inhibitor compound described herein is used in conjunction with a known therapy (e.g., an antibiotic, an antiviral agent, etc.).
- a known therapy e.g., an antibiotic, an antiviral agent, etc.
- An antibiotic can be from any suitable class, such as a penicillin, a tetracycline, a cephalosporin, a quinolone (also known as a fluoroquinolone), a lincomycin, a macrolide, a sulfonamide, a gly copeptide, an aminoglycoside, and a carbapenem.
- antibiotics include, for example, amoxicillin, ampicillin, dicloxacilbn, oxacillin, doxycycbne, demeclocycline, ervacycbne, minocycline, omadacycline, tetracycline, cefotaxime, ceftazidime, cefuroxime, cephalexin, ciprofloxacin, moxifloxacin, clindamycin, lincomycin, metronidazole, azithromycin, clarithromycin, erythromycin, sulfamethoxazole and trimethoprim, amoxicillin and clavulanate, levofloxacin, and a combination thereof.
- An antiviral agent can be from any suitable class, such as a chemokine receptor antagonist, a reverse transcriptase inhibitor, an integrase inhibitor, a protease inhibitor, and a fusion inhibitor.
- antiviral agents include, for example, acyclovir, oseltamivir, zanamivir, peramvir, baloxavir, lopinavir, ritonavir, ivermectin, remdesivir, valacyclovir, cidofovir, foscamet, ganciclovir, valganciclovir, penciclovir, famciclovir, idoxuridine, trifluorothymidine, vidarabine, fomivirsen, amantadine, rimantadine, ribavirin, lamivudine, adefovir dipivoxil, entecavir, telbivudine, clevudine
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be co-administered with an antibiotic or antiviral agent.
- a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered before, concurrently with, or after administration of an antibiotic or antiviral agent.
- One or more than one, e.g., two, three, or more antibiotic or antiviral agents can be administered.
- the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and at least one antibiotic or antiviral agent.
- the disease to be treated is an inflammatory disease.
- an inflammatory disease is that which causes inflammation in at least one tissue.
- Inflamed tissue includes, e.g., tissue from the gastrointestinal system, pulmonary system, skin, musculature, joints, nervous system, and a combination thereof.
- Typical inflammatory diseases include, for example, arthritis (including rheumatoid arthritis, osteoarthritis, and psoriatic arthritis), gut inflammation, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, inflammatory bowel disease (IBD), Alzheimer’s disease, Parkinson’s disease, and bursitis.
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be co-administered with an anti-inflammatory agent.
- the anti-inflammatory agent can be from any suitable class, such as a nonsteroidal anti-inflammatory drug (NSAID) (e.g., a nonselective COX inhibitor, a selective COX2 inhibitor).
- NSAID nonsteroidal anti-inflammatory drug
- anti inflammatory agents include, for example, celecoxib, etoricoxib, valdecoxib, aspirin, diclofenac, ibuprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, diflunisal, naproxen, phenylbutazone, piroxicam, sulindac, mefenamic acid, etodolac, meloxicam, nambumetone, oxaprozin, tolmetin, acetaminophen, duloxetine, and a combination thereof.
- a STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered before, concurrently with, or after administration of an anti-inflammatory agent.
- One or more than one, e.g., two, three, or more anti-inflammatory agents can be administered.
- the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and at least one anti-inflammatory agent.
- the disease associated with increased activity of STAT3 protein is cancer.
- the type of cancer to be treated or prevented is not particularly limited, but in certain aspects, the cancer is characterized as having increased STAT3 activity relative to normal tissue of the same type. See, for example, Garcia et ak, Cell Growth Differ, 1997, 8 (12), 1267-1276; Watson et ak, Br J Cancer, 1995, 71(4), 840-844; Huang et ak, Gynecol Oncol, 2000, 79(1), 67-73; Dhir et ak, Prostate, 2002, 51(4), 241-246; Mora et ak, Cancer Res, 2002, 62(22), 6659-6666; Corvinus et ak, Neoplasia, 2005, 7(6), 545-555; Guo et ak,
- STAT3 is constitutively active in over 40% of all breast cancers, particularly in triple-negative breast cancers which lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/Neu) (Banerjee et ak, Int J Cancer, 2016, 138(11), 2570-2578).
- ER estrogen receptor
- PR progesterone receptor
- HER2/Neu human epidermal growth factor receptor 2
- cancers including cancerous cells and tissue, of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, or adrenals.
- cancers include solid tumor, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,
- the cancer is breast cancer, prostate cancer, pancreatic cancer, or leukemia.
- Anti-cancer activity can be measured by any suitable method, including the assays described herein.
- the STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent) and/or radiation therapy.
- the method comprises administering an amount of a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof that is effective to sensitize the cancer cells to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy).
- a STAT3 inhibitor compound including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered before, concurrently with, or after administration of another anti-cancer agent (e.g., a chemotherapeutic agent).
- another anti-cancer agent e.g., a chemotherapeutic agent
- One or more than one, e.g., two, three, or more anti-cancer agents can be administered.
- the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and at least one anti-cancer agent (e.g., chemotherapeutic agent).
- anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes (e.g., pacbtaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine,
- a method of treating a disease associated with increased activity of STAT3 protein comprising administering to a subject in need thereof a phenol group- containing compound or a pharmaceutically acceptable salt thereof, wherein the phenol group-containing compound has a core structural residue selected from the group consisting of formula (la)
- Aspect (2) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (la) that forms formula (la-1) wherein
- R 1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido
- R 2 is selected from the group consisting of wherein
- R 3 is heterocyclyl
- R 4 is aryl, heteroaryl, or alkenyl
- R 5 is haloalkyl or alkenyl
- R 6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl
- R 7 is H or alkyl
- R 8 is aryl or heteroaryl, each of which is optionally substituted
- R 9 is alkyl or haloalkyl
- X 3 is NH or O
- X 4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof.
- Aspect (3) The method of aspect (2), wherein R 2 is selected from the group consisting of
- Aspect (4) The method of aspect (3), wherein the compound of formula (la-1) is selected from the group consisting of STND-5, STND-8, STND-9, STND-24, STND-25, STND-29, STND-33, STND-34, STND-35, STND-36, STND-37, STND-38, STND-39, STND-40, STND-41, STND-42, STND-43, STND-44, STND-45, STND-46, and STND-47, or a pharmaceutically acceptable salt thereof.
- Aspect (5) The method of aspect (4), wherein the compound of formula (la-1) is selected from the group consisting of STND-9, STND-25, and STND-34, or a pharmaceutically acceptable salt thereof.
- Aspect (11) The method of aspect (10), wherein the compound of formula (Ie-1) is selected from the group consisting of STND-7, STND-12, STND-16, STND-17, and STND- 18, or a pharmaceutically acceptable salt thereof.
- Aspect (12) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (If) that forms formula (If-1) wherein each instance of R 17 is H, alkyl, r alkyl, n is 1-3, and R 19 is selected from the group consisting of pharmaceutically acceptable salt thereof.
- Aspect (13) The method of aspect (12), wherein the compound of formula (If-1) is selected from the group consisting of STND-6, STND-14, STND-15, and STND-20, or a pharmaceutically acceptable salt thereof.
- Aspect (17) The method of aspect (1), wherein the compound to be administered is selected from the group consisting of STND-3, STND-4, and STND-19, or a pharmaceutically acceptable salt thereof.
- Aspect (18) The method of any one of aspects (l)-(l 7), wherein the disease associated with increased activity of STAT3 protein is cancer.
- Aspect (19) The method of aspect (18), wherein the cancer is breast cancer, prostate cancer, pancreatic cancer, or leukemia.
- Aspect (20) The method of any one of aspects (l)-(l 7), wherein the disease associated with increased activity of STAT3 protein is a bacterial or viral infection.
- Aspect (21) The method of aspect (20), wherein the bacterial infection is tuberculosis.
- Aspect (22) The method of aspect (20), wherein the viral infection is by a coronavirus.
- Aspect (23) The method of any one of aspects (l)-(l 7), wherein the disease associated with increased activity of STAT3 protein is an inflammatory disease.
- Aspect (24) The method of aspect (23), wherein the inflammatory disease causes inflammation in at least one tissue selected from the group consisting of a gastrointestinal system, a pulmonary system, skin, musculature, joints, a nervous system, and a combination thereof.
- R 1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido
- R 2 is selected from the group consisting of
- R 3 is heterocyclyl
- R 4 is aryl, heteroaryl, or alkenyl
- R 5 is haloalkyl or alkenyl
- R 6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl,
- R 7 is H or alkyl
- R 8 is aryl or heteroaryl, each of which is optionally substituted
- R 9 is alkyl or haloalkyl
- X 3 is NH or O
- X 4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof, provided that the compound of formula (la-1) is not STND-5, STND-8, STND-9, STND-24, STND-25, STND-35, or STND-36.
- Aspect (26) The compound of aspect (25) that is selected from the group consisting of STND-29, STND-33, STND-34, STND-37, STND-38, STND-39, STND-40, STND-41, STND-42, STND-43, STND-44, STND-45, STND-46, and STND-47, or a pharmaceutically acceptable salt thereof, preferably STND-29, STND-33, STND-34, STND- 37, STND-38, STND-39, STND-40, STND-41, STND-42, STND-46, or STND-47.
- Aspect (27) A compound selected from the group consisting of a compound of formula (Ib-1) a compound of formula (Ic-1)
- R 11 is OH (STND-30) or
- a pharmaceutical composition comprising a compound of any one of aspects (25)-(27) and a pharmaceutically acceptable carrier.
- Aspect (29) A method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein comprising administering to a subject in need thereof a compound of any one of aspects (25)-(27) or a pharmaceutically acceptable salt thereof.
- STAT3 signal transducer and activator of transcription 3
- Exemplary STAT3 N-domain inhibitor compounds can be prepared in accordance with the following reaction schemes.
- FIG. 1 is a reaction scheme of preparing STND-25.
- DIC is N,N' - diisopropylcarbodiimide.
- FIG. 2 is a reaction scheme of preparing STND-27.
- DIEA is N.N'- diisopropylethylamine.
- FIG. 3 is a reaction scheme of preparing STND-28.
- FIG. 4 is a reaction scheme of preparing STND-29.
- FIG. 5 is a reaction scheme of preparing STND-30.
- FIG. 6 is a reaction scheme of preparing STND-31.
- FIG. 7 is a reaction scheme of preparing STND-33.
- FIG. 8 is a reaction scheme of preparing STND-34.
- TMSC1 is chlorotrimethylsilane.
- FIG. 9 is a reaction scheme of preparing STND-37.
- FIG. 10 is a reaction scheme of preparing STND-38.
- FIG. 11 is a reaction scheme of preparing STND-39.
- FIG. 12 is a reaction scheme of preparing STND-40.
- FIG. 13 is a reaction scheme of preparing STND-42.
- FIG. 14 is a reaction scheme of preparing STND-43.
- FIG. 15 is a reaction scheme of preparing STND-44.
- FIG. 16 is a reaction scheme of preparing STND-45.
- FIG. 17 is a reaction scheme of preparing STND-46.
- FIG. 18 is a reaction scheme of preparing STND-47.
- IC50 was determined in the prostate cancer cell line DU145 after 48 hours of exposure to compounds. Binding to the STAT3 N-domain protein (KD) was determined using microscale thermophoresis (MST). The results are set forth in Table 1. The last column of Table 1 identifies the source of each compound, either from a library or designed. Compounds in the SAVI database were first designed by the inventors prior to uploading to the database.
- DU145 cells were treated with compounds STND-2 (3 mM), STND-9 (3 mM), and
- prostate cancer cells (DU145 cell line) were exposed to STND-2, STND-8, and STND-9 for 48 hours, and the number of surviving cells was quantitated using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay (Sigma- Aldrich, St. Louis, MO).
- MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- the N-domain peptide inhibitor ST3H2-A2 (Timofeeva et al., Proc Natl Acad Sci USA, 2013, 110(4), 1267-1272) was used as a positive control.
- the effect of STAT3 N-domain inhibitors of the invention on the growth of prostate cancer is shown in FIG. 22.
- FIG. 23 shows that the compounds of the invention are selectively toxic to prostate tumor cells (DU145) and show very little toxicity to normal prostate epithelial cells (RWPE-1).
- STAT3 N-domain inhibitors STND-9, STND-25, STND-30, STND- 31, and STND-32 are shown in FIG. 24. Cells were exposed to compounds for 48 hours, and the number of surviving cells was quantitated using an MTT assay.
- the cytotoxicity studies demonstrate that the STAT3 N-domain inhibitors of the invention are more than an order of magnitude more potent than previously described peptide inhibitors.
- the inhibitors of the invention show very similar in vitro effects on STAT3 signaling, and consequently can be used for both tumor growth inhibition and modulation of immune responses to tumors and infectious agents.
Abstract
Disclosed is a method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein, such as cancer, comprising administering to a subject in need thereof a STAT3 N-domain inhibitor, such as a phenol group-containing compound as described herein. Also disclosed are compounds of formulas (Ia-1), (Ib-1), (Ic-1), (Id-1), and (Ih-1), as described herein.
Description
SMALL MOLECULE INHIBITORS OF STAT3 N-TERMINAL DOMAIN
AND METHODS OF USE
CROSS-REFERENCE TO A RELATED APPLICATION
[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63/154,440, filed February 26, 2021, which is incorporated by reference for all purposes.
STATEMENT REGARDING
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with Government support under project number Z01BC011306-04 by the National Institutes of Health, National Cancer Institute. The Government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] Signal transducer and activator of transcription 3 (STAT3) activity is a marker for many types of cancer and other diseases, such as diabetic nephropathy, skeletal muscle insulin resistance in type 2 diabetes, endometriosis, depression, asthma, colitis, renal fibrosis, inflammatory bowel disease, systemic lupus erythematosus (SLE), Alzheimer’s disease, Huntington’s disease, and autism. See, e.g., Gkouveris et ak, Journal of Cancer Therapy , 2015; 6: 709-726, WO 2012/159107, and WO 2010/062681. With respect to cancerous cells, aberrant STAT3 is believed to promote tumor cell invasion and metastasis. See, e.g., Yue et ak, Expert Opinion Investig Drugs , 2009; 18(1): 45-56.
[0004] Inhibitors of the N-terminal domain of STAT3 produce different cellular and molecular effects compared to other known STAT3 inhibitors. As a result, inhibition of STAT3 N-terminal domain is considered a promising drug target for the treatment of cancer and infectious diseases. Peptide inhibitors of the domain have been demonstrated to induce immune responses to and clear Mycobacterium tuberculosis in mice and induce expression of proapoptotic genes in cancer cells. However, peptides can suffer from several drawbacks, including limited modes of administration, low selectivity, short life in circulation, and poor cell permeability.
[0005] Thus, there remains an unmet need to provide small molecule compounds that inhibit STAT3 N-terminal domain to be used in a method of treating diseases associated with an overexpression of STAT3.
BRIEF SUMMARY OF THE INVENTION
[0006] The invention provides a method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein comprising administering to a subject in need thereof a compound as described herein, particularly a phenol group-containing small molecule.
[0007] Also provided are novel compounds of formulas (la-1), (Ib-1), (Ic-1), (Id-1), and (Ih-1), as described herein.
[0008] The small molecule compounds have been discovered to be inhibitors of STAT3 N-domain, thereby providing therapeutic treatments for a variety of diseases without specialized modes of administration.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0009] FIG. 1 is a reaction scheme of preparing STND-25. DIC is N.N' - diisopropylcarbodiimide.
[0010] FIG. 2 is a reaction scheme of preparing STND-27. DIEA is N.N' - diisopropylethylamine.
[0011] FIG. 3 is a reaction scheme of preparing STND-28.
[0012] FIG. 4 is a reaction scheme of preparing STND-29.
[0013] FIG. 5 is a reaction scheme of preparing STND-30.
[0014] FIG. 6 is a reaction scheme of preparing STND-31.
[0015] FIG. 7 is a reaction scheme of preparing STND-33.
[0016] FIG. 8 is a reaction scheme of preparing STND-34. TMSC1 is chlorotrimethylsilane.
[0017] FIG. 9 is a reaction scheme of preparing STND-37.
[0018] FIG. 10 is a reaction scheme of preparing STND-38.
[0019] FIG. 11 is a reaction scheme of preparing STND-39.
[0020] FIG. 12 is a reaction scheme of preparing STND-40.
[0021] FIG. 13 is a reaction scheme of preparing STND-42.
[0022] FIG. 14 is a reaction scheme of preparing STND-43.
[0023] FIG. 15 is a reaction scheme of preparing STND-44.
[0024] FIG. 16 is a reaction scheme of preparing STND-45.
[0025] FIG. 17 is a reaction scheme of preparing STND-46.
[0026] FIG. 18 is a reaction scheme of preparing STND-47.
[0027] FIG. 19 is bar graph of percent secreted embryonic alkaline phosphatase (SEAP) of compounds of aspects of the invention incubated with HEK-BLUE IL-10 reporter cells relative to a control set at 100%. From left to right, the bars represent STND-1 (black), STND-3 (stripe), STND-4 (white), STND-5 (black), STND-6 (stripe), STND-7 (white), STND-8 (black), STND-10 (stripe), STND-11 (white), STND-12 (black), STND-13 (stripe), STND-14 (white), STND-15 (black), STND-17 (stripe), STND-19 (white), STND-20 (black), and the control (last column).
[0028] FIG. 20 is a graph showing the inhibition of IL-10 induced STAT3 signaling in HEK-BLUE IL-10 reporter cells versus concentration of STND-9. The data show the cell number, % from untreated (¨) and IL-10-induced STAT3 activity, % of untreated (A). As expected, compounds exhibited cell toxicity (¨). However, inhibition of STAT3 activity (A) was more significant and did not appear to be toxicity-mediated.
[0029] FIG. 21 is a dose response curve of Fnorm (Fi/Fo) versus concentration of STND-9.
[0030] FIG. 22 is graph of DU145 cell numbers after treatment versus concentration of inhibitor for the following compounds: ST3-H2A2 (positive control, STAT3 ND peptide inhibitor) (¨), STND-2 (■), STND-8 (X), and STND-9 (·).
[0031] FIG. 23 is a graph of DU145 cell (solid line) and normal prostate epithelial cells (RWPE-1) (dashed line) cell numbers after treatment versus concentration of inhibitor for the following compounds: STND-9 (¨), STND-25 (■), and STND-34 (·).
[0032] FIG. 24 is a graph of percent KPC95775 cells after treatment versus concentration of inhibitor for the following compounds: STND-9 (¨), STND-25 (■), STND-30 (X), STND-31 (*), and STND-32 (A).
DETAILED DESCRIPTION OF THE INVENTION
[0033] In an aspect, the invention provides a method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein comprising administering to a subject in need thereof a phenol group-containing compound, a compound that is STND-3, STND-4, or STND-19, or a pharmaceutically acceptable salt
thereof. In particular, the phenol group-containing compound is a small molecule of formula (I) in which the remainder of the molecule is para to the OH group on the phenyl ring. The residue of the small molecule is bonded at the para position of the phenyl group through a carbon atom (e.g., that of an alkylene, an alkenyl, or a fused ring), a carbonyl, or an amino moiety. In particular, the phenol group-containing compound has a core structural residue selected from the group consisting of formula (la)
wherein R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, provided that the compound of formula (la) is not
formula (lb)
(Ie), wherein X1 is CH or N, X2 is a bond, CH2, or C(O), and R14 is H or F, formula (If)
wherein each instance of R17 is H, alkyl,
r alkyl, and n is an integer of 1-3, formula (Ig)
(Ih), wherein each of the core structural residues of formulas (la) through (Ih) is bonded to the remainder of the phenol group-containing compound, or a compound or a pharmaceutically acceptable salt thereof that is selected from the group consisting of
[0034] In some aspects of the method, the core structural residue of formula (la) does not include the following compounds:
R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, and
R2 is selected from the group consisting of
wherein
R3 is heterocyclyl,
R4 is aryl, heteroaryl, or alkenyl,
R5 is haloalkyl or alkenyl,
R6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -SC alkenyl, R7 is H or alkyl,
R8 is aryl or heteroaryl, each of which is optionally substituted, R9 is alkyl or haloalkyl,
X3 is NH or O,
X4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof.
[0036] In some aspects of (la-1), R2 is selected from the group consisting of
[0037] Exemplary compounds of formula (la-1) include
,
5,
, or a pharmaceutically acceptable salt thereof.
[0038] In a preferred aspect of the method, the compound of formula (la-1) is STND-9,
STND-25, or STND-34, more preferably STND-25 or STND-34, or any pharmaceutically acceptable salt thereof.
[0039] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (lb) that forms formula (Ib-1)
(Ib-1),
(STND-28), or a pharmaceutically acceptable salt thereof.
[0040] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (Ic) that forms formula (Ic-1)
31) or a pharmaceutically acceptable salt thereof.
[0041] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (Id) that forms formula (Id-1)
(Id-1), wherein
wherein R13 is alkyl, or a pharmaceutically acceptable salt thereof.
[0042] In some aspects of the method, methyl (STND-1) or ethyl (STND-22), or a pharmaceutically acceptable salt thereof.
[0043] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (Ie) that forms formula (Ie-1)
(Ie-1), wherein
X1 is CH or N,
X2 is a bond, CH2, or C(O),
R14 is H or F, and
[0044] Exemplary compounds of formula (Ie-1) include
,
-18, or a pharmaceutically acceptable salt thereof.
[0045] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (If) that forms formula (If-1)
(if-i), wherein each instance of R17 is H, alk l,
R18 is H or alkyl, n is an integer of 1-3, and R19 is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
[0046] Exemplary compounds of formula (If-1) include
, or a pharmaceutically acceptable salt thereof.
[0047] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (Ig) that forms formula (Ig-1)
(Ig-1), wherein
R20 is CH 2 or CH=CH, and
[0049] In some aspects of the method, the phenol group-containing compound has a core structural residue of formula (Ih) that forms formula (Ih-1)
(Ih-1), wherein R22 is selected from the group consisting of
-32, or a pharmaceutically acceptable salt thereof.
[0050] In some aspects, the compound used in the method is selected from the group consisting of
-19, or a pharmaceutically acceptable salt thereof.
[0051] In an aspect, the present invention further provides exemplary compounds of formula (la-1)
wherein
R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, and R2 is selected from the group consisting of
wherein
R3 is heterocyclyl,
R4 is aryl, heteroaryl, or alkenyl,
R5 is haloalkyl or alkenyl,
R6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl,
R7 is H or alkyl,
R8 is aryl or heteroaryl, each of which is optionally substituted,
R9 is alkyl or haloalkyl,
X3 is NH or O,
X4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof provided that the compound of formula (la-1) is not STND-5, STND-8, STND-9, STND-24, STND-25, STND-35, or STND-36, and in some aspects of the invention, the compound of formula (la-1) also is not STND-43, STND-44, or STND-45:
,
[0052] In some aspects of the invention, the genus of formula (la-1) does not include one or more of the following compounds:
[0053] In an aspect, the compound of formula (la-1) preferably is
-33,
or a pharmaceutically acceptable salt thereof.
[0054] In some aspects of the invention, the compound of formula (la-1) is STND-29, STND-33, STND-34, STND-37, STND-38, STND-39, STND-40, STND-41, STND-42,
STND-46, or STND-47, or any pharmaceutically acceptable salt thereof.
[0055] Further provided is a compound selected from the group consisting of a compound of formula (Ib-1)
(Ib-1),
(STND-31), a compound of formula (Id-1)
(Id-1), wherein
a compound of formula (Ih-1)
wherein
or a pharmaceutically acceptable salt thereof.
[0056] In any of the aspects above, the term “alkyl” implies a straight-chain or branched alkyl substituent containing from, for example, from 1 to about 8 carbon atoms, e.g., from about 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms. Examples of alkyl group include methyl, ethyl, «-propyl, isopropyl, «-butyl, vec-butyl. isobutyl, tert-butyl, «-pentyl, isopentyl, «-hexyl, and the like. This definition also applies wherever “alkyl” occurs as part of a group, such as, e.g., in C3-C6 cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl (-C(O)alkyl), alkylcarboxy
(-C(O)Oalkyl), arylalkyl, heteroarylalkyl, etc. The alkyl can be substituted or unsubstituted, as described herein. Even in instances in which the alkyl is an alkylene chain (e.g., -(CH2)n-), the alkyl group can be substituted or unsubstituted.
[0057] In any of the aspects above, the term “alkenyl,” as used herein, means a linear alkenyl substituent containing from, for example, 2 to about 8 carbon atoms (branched alkenyls are about 3 to about 8 carbons atoms), e.g., from 2 to about 6 carbon atoms (branch alkenyls are about 3 to about 6 carbon atoms), from about 3 to about 5 carbon atoms (branched alkenyls are about 3 to about 6 carbons atoms). In accordance with an aspect, the alkenyl group is a C2-C6 alkenyl or C2-C4 alkenyl. Examples of alkenyl group include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1- hexenyl, and the like. The alkenyl can be substituted or unsubstituted, as described herein. [0058] In any of the aspects above, the term “cycloalkyl,” as used herein, means a cyclic alkyl moiety containing from, for example, 3 to about 6 carbon atoms or from 5 to about 6 carbon atoms. Examples of such moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl can be substituted or unsubstituted, as described herein.
[0059] In any of the aspects above, the term “aryl” refers to a mono, bi, or tricyclic carbocycbc ring system having one, two, or three aromatic rings, for example, phenyl, naphthyl, anthracenyl, or biphenyl. The term “aryl” refers to an unsubstituted or substituted aromatic carbocycbc moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. An aryl moiety generally contains from, for example, 6 to about 30 carbon atoms, from 6 to about 18 carbon atoms, from 6 to about 14 carbon atoms, or from 6 to about 10 carbon atoms. It is understood that the term aryl includes carbocycbc moieties that are planar and comprise 4n+2 p electrons, according to HiickeTs Rule, wherein n = 1, 2, or 3. This definition also applies wherever “aryl” occurs as part of a group, such as, e.g., in haloaryl (e.g., monohaloaryl, dihaloaryl, and trihaloaryl), arylalkyl, etc. The aryl can be substituted or unsubstituted, as described herein.
[0060] In any of the aspects above, the term “heterocyclyl” encompasses both heteroaryl groups and heterocycloalkyl groups, as described herein.
[0061] In any of the aspects above, the term “heteroaryl” refers to aromatic 5- or 6- membered monocyclic groups, 9- or 10-membered bicycbc groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings.
Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quatemized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl (thiophenyl), isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. The heteroaryl can be substituted or unsubstituted, as described herein.
[0062] The term “heterocycloalkyl” means a stable, saturated, or partially unsaturated monocyclic, bicyclic, and spiro ring system containing 3 to 7 ring members of carbon atoms and other atoms selected from the group consisting of nitrogen, sulfur, and/or oxygen. In an aspect, a heterocycloalkyl is a 5-, 6-, or 7-membered monocyclic ring and contains one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocycloalkyl may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Examples of such heterocycloalkyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl. The heterocycloalkyl can be substituted or unsubstituted, as described herein. [0063] In any of the aspects above, the term “hydroxy” refers to the group -OH.
[0064] In any of the aspects above, the term “cyano” refers to the group -CN, whereas the term “thiocyano” refers to -SCN.
[0065] In any of the aspects above, the terms “alkoxy” and “cycloalkyloxy” embrace linear or branched alkyl and cycloalkyl groups, respectively, that are attached to a divalent oxygen. The alkyl and cycloalkyl groups are the same as described herein.
[0066] In any of the aspects above, the term “halo” refers to a halogen selected from fluorine, chlorine, bromine, and iodine.
[0067] In any of the aspects above, the term “carboxylato” refers to the group -C(0)OH.
[0068] In any of the aspects above, the term “amino” refers to the group -NH2. The term “alkylamino” refers to -NHR, whereas the term “dialkylamino” refers to -NRR'. R and R' are the same or different and each is a substituted or unsubstituted alkyl group, as described herein.
[0069] In any of the aspects above, the term “amido” refers to the group -C(0)NRR', which R and R' are the same or different and each is hydrogen or a substituted or unsubstituted alkyl group, as described herein.
[0070] In other aspects, any substituent that is not hydrogen (e.g., alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) can be an optionally substituted moiety. The substituted moiety typically comprises at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position (e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.). When an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy, and others, the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g.,
2-, 3-, 4-, 5-, and/or 6-position wherein the 1-position is the point of attachment of the aryl group in the compound of the present invention. Suitable substituents for any non-hydrogen substituent include, e.g., halo, alkyl, alkenyl, hydroxy, nitro, cyano, thiocyano, amino, alkylamino, alkoxy, aryloxy, aralkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido, haloalkylamido, aryl, heteroaryl, and heterocycloalkyl, each of which is described herein. In some instances, the substituent is at least one (e.g., 1 or 2) alkyl, halo, and/or haloalkyl.
[0071] In any of the aspects above, whenever a range of the number of atoms in a structure is indicated (e.g., a Ci-12, Ci-8, Ci-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., Ci-Cx). 1- 6 carbon atoms (e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, and/or 8 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon
atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, etc., as appropriate).
[0072] The subscript “n” represents the number of methylene repeat units in formula (If). The subscript n is an integer of either 1, 2, or 3.
[0073] The subscript “m” represents the number of methylene repeat units in formula (Ia- 1). The subscript m is an integer from 1-5 (i.e., 1, 2, 3, 4, or 5).
[0074] In any of the aspects above, the phrase “salt” or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. For example, an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid), an organic acid (e.g., formic acid, oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid), an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide), an organic base (e.g., methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine), or an amino acid (e.g., lysine, arginine, or alanine) can be used. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences , 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.
[0075] The terms “co-administered” or “co-administration” used herein refer to simultaneous or sequential administration.
[0076] The Enamine library of in-stock compounds containing almost 2 million entries was used for initial screens that evaluated the binding pockets and identified early hits (e.g., STND-1 through STND-7). Additional hits came from screening larger Enamine diversity libraries containing 5 and 15 million compounds (e.g., STND-15 through STND-18). The highest scoring hits have been used for identification of potential binders in similarity searches. Search engine GIGA (www.molsoft.com/giga-search.html) was used for screening
of the REAL database of 1.2 billion synthesizable compounds from Enamine (enamine.net/bbrary-synthesis/real-compounds/real-database).
[0077] The Quantitative Neighborhoods of Atoms (QNA) methodology (Filimonov et al., SAR QSAR Environ Res, 2009, 20(7-8), 679-709) was used for screening SAVI (Synthetically Accessible Virtual Inventory). SAVI has been recently generated using CHMTRN (CHeMistry TRaNslator) adaptation for a knowledge-based forward synthesis computer program (Judson et al., J Chem Inf Model, 2020, 60(1), 3336-3341). The latest version of SAVI used in the screens contains 1.75 billion entries and first became publicly available November 11, 2020 (Patel et al., Scientific Data, November 11, 2020, 7(384), 1-14).
Libraries of potential hits from REAL and SAVI were subjected to a three-step docking screen procedure that has proven to reliably identify effective binders. Promising compounds from these screens and related analogs were synthesized using one-step reactions and tested for protein binding and STAT3-dependent tumor cell grows inhibition. It was discovered that the para-phenolic group contributes significantly to the binding. Phenol fits well in the binding pocket and forms hydrogen bonds with the amide carbonyl of Glul 11 and the guanido group of Argll4, thus adding significantly to the interaction energy.
[0078] Compounds described herein can be purchased commercially or synthetically prepared. General methods for preparing compounds of the invention are described herein. [0079] The methods described herein comprise administering, to a subject in need thereof, a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition. In particular, a pharmaceutical composition comprises at least one STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available. Typically, the pharmaceutically acceptable carrier is one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.
[0080] The pharmaceutical compositions can be administered as oral, sublingual, transdermal, subcutaneous, topical, absorption through epithelial or mucocutaneous linings, intravenous, intranasal, intraarterial, intraperitoneal, intramuscular, intratumoral, peritumoral,
intraperitoneal, intrathecal, rectal, vaginal, or aerosol formulations. In some aspects, the pharmaceutical composition is administered orally or intravenously.
[0081] In accordance with any of the aspects, the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered orally to a subject in need thereof. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice and include an additive, such as cyclodextrin (e.g., a-, b-, or g-cyclodextrin, hydroxypropyl cyclodextrin) or polyethylene glycol (e.g., PEG400); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions and gels.
Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
[0082] Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a salt thereof can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related
sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2, 2-dimethyl- 1,3- dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
[0083] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
[0084] The parenteral formulations typically contain from about 0.5 to about 25% by weight of the inhibitors in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and
suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
[0085] The inhibitors can be made into injectable formulations. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, }. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).
[0086] Topically applied compositions are generally in the form of liquids (e.g., mouthwash), creams, pastes, lotions, gels, and transdermal patches. Topical administration includes application to the skin and oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa. In some aspects, the composition contains at least one active component and a suitable vehicle or carrier. It can also contain other components, such as an anti-irritant. The carrier can be a liquid, solid or semi-solid. In aspects, the composition is an aqueous solution, such as a mouthwash. Alternatively, the composition can be a dispersion, emulsion, gel, lotion, or cream vehicle for the various components. In one aspect, the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral. The liquid vehicle can include other materials, such as buffers, alcohols, glycols, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site. In aspects of the invention, the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin, and silicone based materials.
[0087] The STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
[0088] The dose administered to the subject, particularly human and other mammals, in accordance with the present invention should be sufficient to affect the desired response.
One skilled in the art will recognize that dosage will depend upon a variety of factors, including the age, condition or disease state, predisposition to disease, genetic defect or defects, and body weight of the mammal. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular inhibitor and the desired effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.
[0089] The inventive methods comprise administering an effective amount of a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof. An “effective amount” means an amount sufficient to show a meaningful benefit in an individual, cell, or tissue to be treated. A meaningful benefit includes, for example, detectably treating, relieving, healing, preventing, delaying the onset of, ameliorating, or lessening one or more symptoms of a disease mediated by overexpression of STAT3 (e.g., inflammation, fluid accumulation), inhibiting, arresting development, preventing, or halting further development of a viral infection or disease, promoting at least one aspect of tumor cell cytotoxicity (e.g., inhibition of growth, inhibiting survival of a cancer cell, reducing proliferation, reducing size and/or mass of a tumor (e.g., solid tumor)). The meaningful benefit observed in the subject can be to any suitable degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more or anything in between each of these percentages). In some aspects, one or more symptoms of the disease (e.g., disease caused by a bacterium or virus, cancer) are treated, prevented, reduced, halted, or eliminated subsequent to administration of a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, thereby effectively treating the disease (e.g., disease caused by a bacterium or virus, cancer) to at least some degree.
[0090] Effective amounts can vary depending upon the biological effect desired in the individual, condition to be treated, and/or the specific characteristics of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, and the individual. In this respect, any suitable dose of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered to the subject (e.g.,
human), according to the type of disease (e.g., disease caused by a bacterium or virus, cancer) to be treated. Various general considerations taken into account in determining the “effective amount” are known to those of skill in the art and are described, e.g., in Gilman et ak, eds., Goodman and Gilman’s: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington’s Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa., 1990, each of which is herein incorporated by reference. The dose of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof desirably comprises about 0.01 mg per kilogram (kg) of the body weight of the subject (mg/kg) or more (e.g., about 0.05 mg/kg or more, 0.1 mg/kg or more, 0.5 mg/kg or more, 1 mg/kg or more, 2 mg/kg or more, 5 mg/kg or more, 10 mg/kg or more, 15 mg/kg or more, 20 mg/kg or more, 30 mg/kg or more, 40 mg/kg or more, 50 mg/kg or more, 75 mg/kg or more, 100 mg/kg or more, 125 mg/kg or more, 150 mg/kg or more, 175 mg/kg or more, 200 mg/kg or more, 225 mg/kg or more, 250 mg/kg or more, 275 mg/kg or more, 300 mg/kg or more, 325 mg/kg or more, 350 mg/kg or more, 375 mg/kg or more, 400 mg/kg or more, 425 mg/kg or more, 450 mg/kg or more, or 475 mg/kg or more) per day. Typically, the dose will be about 500 mg/kg or less (e.g., about 475 mg/kg or less, about 450 mg/kg or less, about 425 mg/kg or less, about 400 mg/kg or less, about 375 mg/kg or less, about 350 mg/kg or less, about 325 mg/kg or less, about 300 mg/kg or less, about 275 mg/kg or less, about 250 mg/kg or less, about 225 mg/kg or less, about 200 mg/kg or less, about 175 mg/kg or less, about 150 mg/kg or less, about 125 mg/kg or less, about 100 mg/kg or less, about 75 mg/kg or less, about 50 mg/kg or less, about 40 mg/kg or less, about 30 mg/kg or less, about 20 mg/kg or less, about 15 mg/kg or less, about 10 mg/kg or less, about 5 mg/kg or less, about 2 mg/kg or less, about 1 mg/kg or less, about 0.5 mg/kg or less, or about 0.1 mg/kg or less). Any two of the foregoing endpoints can be used to define a close- ended range, or a single endpoint can be used to define an open-ended range.
[0091] For purposes of the present invention, the term “subject” preferably is directed to a mammal. Mammals include, but are not limited to, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perissodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Cebids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is a human.
[0092] STAT3 has been long considered a promising drug target due to its involvement in proliferation of tumor cells, inflammation, and immune responses. See, e.g., Bharadwaj et al., Pharmacol Rev 2020, 72 (2), 486-526; Huynh et al., Nat Rev Cancer 2019, 19 (2), 82-96; Gkouveris et al., Journal of Cancer Therapy , 2015, 6, 709-726; WO 2012/159107, and WO 2010/062681. An aberrant STAT3 pathway has also been shown to play a critical role in the pathogenesis of SARS-CoV-2 (Matsuyama et al., Cell Death Differ, October 9, 2020,
27(12), 3209-3225). However, the N-terminal domain of STAT3 has emerged as a very different target (Hu et al ,Mol Cell Biol, 2015, 35(19), 3284-300) and inhibitors of the domain produce significantly different cellular and molecular effects compared to other STAT3 inhibitors (Timofeeva et al., ACS Chem Biol, 2007, 2(12), 799-809; and Timofeeva et al., Proc Natl Acad Sci USA, 2013, 110(A), 1267-1272). A functional aspect is that inhibitors of STAT3 N-domain impact not only tumor cells proliferation, but also immune responses to tumors and bacterial and viral pathogens. Thus, in an aspect, a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), inhibits and/or reduces STAT3 activity, preferably STAT3 N-domain activity, in a cell, such as a cancer cell. The method includes contacting a cell with a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof, whereby the activity of STAT3, particularly STAT3 N-domain, in the cell is inhibited. The STAT3 activity can be measured by any method, including the assays described herein.
[0093] Inhibition of STAT3 has been described in the art as a viable treatment of diseases that are characterized as overexpressing STAT3. In particular, peptide STAT3 N-domain inhibitors have been shown to up-regulate expression of several proapoptotic proteins, in particular c-Fos (Timofeeva et al., Proc Natl Acad Sci USA, 2013, 110 (4), 1267-1272). Western blot analysis of c-Fos expression has shown that the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), effectively increase c-Fos expression in prostate cancer cells. Thus, the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), can be administered to a subject in need thereof as part of a treatment method for diseases that overexpress STAT3 (e.g., a disease caused by a bacterium or virus, cancer). In particular, the disease associated with increased activity of STAT3 protein can be, for example, a bacterial infection, a viral infection, an inflammatory disease, or cancer.
[0094] In an aspect, the disease can be a bacterial infection (including a disease caused by a bacterial infection) or a viral infection (including a disease caused by a viral infection).
[0095] The bacterial infection can be caused by, for example, Staphylococcus aureus, gram positive methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus saprophyticus, Pseudomonas aeruginosa, Listeria monocytogenes, Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Haemophilus influenzae, Helicobacter pylori, Salmonella, Shigella, Clostridium, Enterobacter aerogenes, gram negative Escherichia coli, Clostridium difficile, or a combination thereof. Diseases caused by a bacterial infection include, e.g., tuberculosis, gastritis, meningitis, gonorrhea, pneumonia, bacterial food poisoning, strep throat, cellulitis, wound infections, and toxic shock syndrome. In some aspects of the method, the bacterial infection is tuberculosis. [0096] The viral infection can be, e.g., influenza virus (e.g., H1N1, H1N2, and H5N1), gastroenteritis, hepatitis virus, herpes simplex virus, West Nile virus, Ebola, human papillomavirus, coronavirus, chickenpox virus, flavivirus, togavirus, levivirus, norovirus, rotavirus, adenovirus, parvovirus, poliovirus, or a combination thereof. The coronavirus can be, for example, SARS-CoV, SARS-CoV-2, or MERS-CoV. Preferably, the disease associated with increased activity of STAT3 protein is SARS-CoV-2. Diseases caused by a viral infection include, e.g., coronavirus disease (COVID-19), severe acute respiratory syndrome (SARS) virus, Middle East respiratory syndrome (MERS), a respiratory disease (e.g., pneumonia, bronchitis, pleural effusion), an inflammatory disease (e.g., inflammation, COVID-19-induced inflammation, pediatric multi-system inflammatory syndrome (PMIS)), reproductive and respiratory syndrome virus (PRRSV), equine arteritis virus (EAV), or gastroenteritis.
[0097] In some aspects when the disease associated with increased activity of STAT3 protein is a bacterial infection (including a disease caused by a bacterial infection) or a viral infection (including a disease caused by a viral infection), the inhibitor compound described herein is used in conjunction with a known therapy (e.g., an antibiotic, an antiviral agent, etc.). An antibiotic can be from any suitable class, such as a penicillin, a tetracycline, a cephalosporin, a quinolone (also known as a fluoroquinolone), a lincomycin, a macrolide, a sulfonamide, a gly copeptide, an aminoglycoside, and a carbapenem. Examples of antibiotics include, for example, amoxicillin, ampicillin, dicloxacilbn, oxacillin, doxycycbne, demeclocycline, ervacycbne, minocycline, omadacycline, tetracycline, cefotaxime, ceftazidime, cefuroxime, cephalexin, ciprofloxacin, moxifloxacin, clindamycin, lincomycin, metronidazole, azithromycin, clarithromycin, erythromycin, sulfamethoxazole and trimethoprim, amoxicillin and clavulanate, levofloxacin, and a combination thereof. An
antiviral agent can be from any suitable class, such as a chemokine receptor antagonist, a reverse transcriptase inhibitor, an integrase inhibitor, a protease inhibitor, and a fusion inhibitor. Examples of antiviral agents include, for example, acyclovir, oseltamivir, zanamivir, peramvir, baloxavir, lopinavir, ritonavir, ivermectin, remdesivir, valacyclovir, cidofovir, foscamet, ganciclovir, valganciclovir, penciclovir, famciclovir, idoxuridine, trifluorothymidine, vidarabine, fomivirsen, amantadine, rimantadine, ribavirin, lamivudine, adefovir dipivoxil, entecavir, telbivudine, clevudine, interferons, imiquimod, pleconaril, maraviroc, enfuvirtide, zidovudine, didanosine, zalcitabine, stavudine, abacavir, emtricitabine, tenofovir disoproxil fumarate, nevirapine, delavirdine, efavirenz, raltegravir, saquinavir, indinavir, ritonavir, nelfmavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir, and a combination thereof.
[0098] In certain aspects of the method, the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be co-administered with an antibiotic or antiviral agent. A STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered before, concurrently with, or after administration of an antibiotic or antiviral agent. One or more than one, e.g., two, three, or more antibiotic or antiviral agents can be administered. Accordingly, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and at least one antibiotic or antiviral agent.
[0099] In an aspect, the disease to be treated is an inflammatory disease. Generally, an inflammatory disease is that which causes inflammation in at least one tissue. Inflamed tissue includes, e.g., tissue from the gastrointestinal system, pulmonary system, skin, musculature, joints, nervous system, and a combination thereof. Typical inflammatory diseases include, for example, arthritis (including rheumatoid arthritis, osteoarthritis, and psoriatic arthritis), gut inflammation, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, inflammatory bowel disease (IBD), Alzheimer’s disease, Parkinson’s disease, and bursitis.
[0100] In certain aspects of the method, the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be co-administered with an anti-inflammatory agent. The anti-inflammatory
agent can be from any suitable class, such as a nonsteroidal anti-inflammatory drug (NSAID) (e.g., a nonselective COX inhibitor, a selective COX2 inhibitor). Examples of anti inflammatory agents include, for example, celecoxib, etoricoxib, valdecoxib, aspirin, diclofenac, ibuprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, diflunisal, naproxen, phenylbutazone, piroxicam, sulindac, mefenamic acid, etodolac, meloxicam, nambumetone, oxaprozin, tolmetin, acetaminophen, duloxetine, and a combination thereof. [0101] A STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered before, concurrently with, or after administration of an anti-inflammatory agent. One or more than one, e.g., two, three, or more anti-inflammatory agents can be administered. Accordingly, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof and at least one anti-inflammatory agent.
[0102] In some aspects, the disease associated with increased activity of STAT3 protein is cancer. The type of cancer to be treated or prevented is not particularly limited, but in certain aspects, the cancer is characterized as having increased STAT3 activity relative to normal tissue of the same type. See, for example, Garcia et ak, Cell Growth Differ, 1997, 8 (12), 1267-1276; Watson et ak, Br J Cancer, 1995, 71(4), 840-844; Huang et ak, Gynecol Oncol, 2000, 79(1), 67-73; Dhir et ak, Prostate, 2002, 51(4), 241-246; Mora et ak, Cancer Res, 2002, 62(22), 6659-6666; Corvinus et ak, Neoplasia, 2005, 7(6), 545-555; Guo et ak,
Am J Transl Res , 2009, 1(3), 283-290; Schaefer et ak, Oncogene, 2002, 21(13), 2058-2065; and Wei et ak, Oncogene, 2003, 22(3), 319-329. For example, STAT3 is constitutively active in over 40% of all breast cancers, particularly in triple-negative breast cancers which lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/Neu) (Banerjee et ak, Int J Cancer, 2016, 138(11), 2570-2578).
[0103] Examples of cancer treatable with the inventive method include cancers, including cancerous cells and tissue, of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, or adrenals. More particularly, cancers include solid tumor, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio
sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi’s sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, retinoblastoma, a blood-borne tumor, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma. See, e.g., Harrison ’s Principles of Internal Medicine, Eugene Braunwald et ak, eds., pp. 491-762 (15th Ed. 2001). In some aspects, the cancer is breast cancer, prostate cancer, pancreatic cancer, or leukemia. Anti-cancer activity can be measured by any suitable method, including the assays described herein.
[0104] In certain aspects of this method, the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent) and/or radiation therapy. In an aspect, the method comprises administering an amount of a STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof that is effective to sensitize the cancer cells to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy). A STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or a pharmaceutically acceptable salt thereof can be administered before, concurrently with, or after administration of another anti-cancer agent (e.g., a chemotherapeutic agent).
[0105] One or more than one, e.g., two, three, or more anti-cancer agents can be administered. In this regard, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the STAT3 inhibitor compound, including formulas (la) through (Ih) and (la-1) through (Ih-1), or
a pharmaceutically acceptable salt thereof and at least one anti-cancer agent (e.g., chemotherapeutic agent).
[0106] Examples of anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes (e.g., pacbtaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab, panitumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), enzymes (e.g., L- Asparaginase), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), a CDK4/6 inhibitor (e.g., abemaciclib, palbocicbb, ribocicbb), anti-cancer hormonal agents (e.g., tamoxifen, fulvestrant, raloxifene, leuprobde, bicalutamide, granisetron, flutamide, goserebn), aromatase inhibitors (e.g., exemestane, letrozole, and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX-2) inhibitors, immune checkpoint inhibitors (e.g., anti-PDl, anti- CTLA4, and anti-PD-Ll), cellular immunotherapy (e.g., chimeric antigen receptor T cell therapy, tumor-infiltrating lymphocyte therapy), or any combination thereof.
[0107] The invention is further illustrated by the following aspects.
[0108] Aspect (1) A method of treating a disease associated with increased activity of STAT3 protein comprising administering to a subject in need thereof a phenol group- containing compound or a pharmaceutically acceptable salt thereof, wherein the phenol
group-containing compound has a core structural residue selected from the group consisting of formula (la)
(la), wherein R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, formula (lb)
(Ie), wherein X1 is CH or N, X2 is a bond, CH2, or C(O), and R14 is H or F formula (If)
wherein each instance of R17 is H, alkyl,
r alkyl, and n is an integer of 1-3, formula (Ig)
(Ig), wherein R20 is CH2 or CH=CH, and formula (Ih)
(Ih), wherein each of the core structural residues of formulas (la) through (Ih) is bonded to the remainder of the phenol group-containing compound, or a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
[0109] Aspect (2) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (la) that forms formula (la-1)
wherein
R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, and R2 is selected from the group consisting of
wherein
R3 is heterocyclyl,
R4 is aryl, heteroaryl, or alkenyl, R5 is haloalkyl or alkenyl,
R6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl,
R7 is H or alkyl,
R8 is aryl or heteroaryl, each of which is optionally substituted,
R9 is alkyl or haloalkyl,
X3 is NH or O,
X4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
[0111] Aspect (4) The method of aspect (3), wherein the compound of formula (la-1) is selected from the group consisting of STND-5, STND-8, STND-9, STND-24, STND-25, STND-29, STND-33, STND-34, STND-35, STND-36, STND-37, STND-38, STND-39, STND-40, STND-41, STND-42, STND-43, STND-44, STND-45, STND-46, and STND-47, or a pharmaceutically acceptable salt thereof.
[0112] Aspect (5) The method of aspect (4), wherein the compound of formula (la-1) is selected from the group consisting of STND-9, STND-25, and STND-34, or a pharmaceutically acceptable salt thereof.
[0113] Aspect (6) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (lb) that forms formula (Ib-1)
(Ib-1), wherein R10 is selected from the group consisting of
pharmaceutically acceptable salt thereof. [0114] Aspect (7) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (Ic) that forms formula (Ic-1)
(STND-31) or a pharmaceutically acceptable salt thereof.
[0115] Aspect (8) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (Id) that forms formula (Id-1)
(Id-1), wherein
wherein R13 is alkyl, or a pharmaceutically acceptable salt thereof.
[0116] Aspect (9) The method of aspect (8), wherein is methyl (STND-1) or ethyl (STND-22), or a pharmaceutically acceptable salt thereof. [0117] Aspect (10) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (Ie) that forms formula (Ie-1)
(Ie-1), wherein X1 is CH or N, X2 is a bond, CH2, or C(O), R14 is H or F, and R15 is selected from the group consisting of
pharmaceutically acceptable salt thereof.
[0118] Aspect (11) The method of aspect (10), wherein the compound of formula (Ie-1) is selected from the group consisting of STND-7, STND-12, STND-16, STND-17, and STND- 18, or a pharmaceutically acceptable salt thereof.
[0119] Aspect (12) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (If) that forms formula (If-1)
wherein each instance of R17 is H, alkyl,
r alkyl, n is 1-3, and R19 is selected from the group consisting of
pharmaceutically acceptable salt thereof.
[0120] Aspect (13) The method of aspect (12), wherein the compound of formula (If-1) is selected from the group consisting of STND-6, STND-14, STND-15, and STND-20, or a pharmaceutically acceptable salt thereof.
[0121] Aspect (14) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (Ig) that forms formula (Ig-1)
(Ig-1), wherein R20 is CTk or CH=CH, and R21 is selected from the group consisting of
pharmaceutically acceptable salt thereof.
[0122] Aspect (15) The method of aspect (14), wherein the compound of formula (Ig-1) is selected from the group consisting of STND-10 and STND-13 or a pharmaceutically acceptable salt thereof.
[0123] Aspect (16) The method of aspect (1), wherein the phenol group-containing compound has a core structural residue of formula (Ih) that forms formula (Ih-1)
(Ih-1), wherein R22 is selected from the group consisting of
pharmaceutically acceptable salt thereof.
[0124] Aspect (17) The method of aspect (1), wherein the compound to be administered is selected from the group consisting of STND-3, STND-4, and STND-19, or a pharmaceutically acceptable salt thereof.
[0125] Aspect (18) The method of any one of aspects (l)-(l 7), wherein the disease associated with increased activity of STAT3 protein is cancer.
[0126] Aspect (19) The method of aspect (18), wherein the cancer is breast cancer, prostate cancer, pancreatic cancer, or leukemia.
[0127] Aspect (20) The method of any one of aspects (l)-(l 7), wherein the disease associated with increased activity of STAT3 protein is a bacterial or viral infection.
[0128] Aspect (21) The method of aspect (20), wherein the bacterial infection is tuberculosis.
[0129] Aspect (22) The method of aspect (20), wherein the viral infection is by a coronavirus.
[0130] Aspect (23) The method of any one of aspects (l)-(l 7), wherein the disease associated with increased activity of STAT3 protein is an inflammatory disease.
[0131] Aspect (24) The method of aspect (23), wherein the inflammatory disease causes inflammation in at least one tissue selected from the group consisting of a gastrointestinal system, a pulmonary system, skin, musculature, joints, a nervous system, and a combination thereof.
(la-1), wherein
R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, and R2 is selected from the group consisting of
wherein
R3 is heterocyclyl,
R4 is aryl, heteroaryl, or alkenyl,
R5 is haloalkyl or alkenyl,
R6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl,
R7 is H or alkyl,
R8 is aryl or heteroaryl, each of which is optionally substituted,
R9 is alkyl or haloalkyl,
X3 is NH or O,
X4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof, provided that the compound of formula (la-1) is not STND-5, STND-8, STND-9, STND-24, STND-25, STND-35, or STND-36.
[0133] Aspect (26) The compound of aspect (25) that is selected from the group consisting of STND-29, STND-33, STND-34, STND-37, STND-38, STND-39, STND-40, STND-41, STND-42, STND-43, STND-44, STND-45, STND-46, and STND-47, or a pharmaceutically acceptable salt thereof, preferably STND-29, STND-33, STND-34, STND- 37, STND-38, STND-39, STND-40, STND-41, STND-42, STND-46, or STND-47.
[0134] Aspect (27) A compound selected from the group consisting of a compound of formula (Ib-1)
a compound of formula (Ic-1)
(Ic-1),
(Ih-1),
wherein pharmaceutically acceptable salt thereof.
[0135] Aspect (28) A pharmaceutical composition comprising a compound of any one of aspects (25)-(27) and a pharmaceutically acceptable carrier.
[0136] Aspect (29) A method of treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein comprising administering to a subject in need thereof a compound of any one of aspects (25)-(27) or a pharmaceutically acceptable salt thereof.
[0137] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
EXAMPLE 1
[0138] Exemplary STAT3 N-domain inhibitor compounds can be prepared in accordance with the following reaction schemes.
[0139] FIG. 1 is a reaction scheme of preparing STND-25. DIC is N,N' - diisopropylcarbodiimide.
[0140] FIG. 2 is a reaction scheme of preparing STND-27. DIEA is N.N'- diisopropylethylamine.
[0141] FIG. 3 is a reaction scheme of preparing STND-28.
[0142] FIG. 4 is a reaction scheme of preparing STND-29.
[0143] FIG. 5 is a reaction scheme of preparing STND-30.
[0144] FIG. 6 is a reaction scheme of preparing STND-31.
[0145] FIG. 7 is a reaction scheme of preparing STND-33.
[0146] FIG. 8 is a reaction scheme of preparing STND-34. TMSC1 is chlorotrimethylsilane.
[0147] FIG. 9 is a reaction scheme of preparing STND-37.
[0148] FIG. 10 is a reaction scheme of preparing STND-38.
[0149] FIG. 11 is a reaction scheme of preparing STND-39.
[0150] FIG. 12 is a reaction scheme of preparing STND-40.
[0151] FIG. 13 is a reaction scheme of preparing STND-42.
[0152] FIG. 14 is a reaction scheme of preparing STND-43.
[0153] FIG. 15 is a reaction scheme of preparing STND-44.
[0154] FIG. 16 is a reaction scheme of preparing STND-45.
[0155] FIG. 17 is a reaction scheme of preparing STND-46.
[0156] FIG. 18 is a reaction scheme of preparing STND-47.
EXAMPLE 2
[0157] This example demonstrates the STAT3 N-domain specificity and cytotoxicity of exemplary compounds in an aspect of the invention.
[0158] IC50 was determined in the prostate cancer cell line DU145 after 48 hours of exposure to compounds. Binding to the STAT3 N-domain protein (KD) was determined using microscale thermophoresis (MST). The results are set forth in Table 1. The last column of Table 1 identifies the source of each compound, either from a library or designed. Compounds in the SAVI database were first designed by the inventors prior to uploading to the database.
EXAMPLE 3
[0159] This example demonstrates that exemplary STAT3 N-domain binders of the invention inhibit STAT3 signaling in HEK-BLUE IL-10 reporter cells.
[0160] Inhibition of 11-10- induced secretion of embryonic alkaline phosphatase in the reporter cell line, HEK-Blue IL10 cells (Invivogen, www.invivogen.com/hek-blue-il 10) was measured. Cells (-70.000 cells/mL) were incubated with IL-10 (0.1 ng/ml) without an inhibitor (control) or with 500 mM of compound by measuring the secreted embryonic alkaline phosphatase (SEAP) levels induced after 24 hours incubation. As seen in FIG. 19,
compounds of the invention not only effectively interfered with STAT3 activity, but the degree of inhibition by different compounds correlated well with the binding score and compound’s toxicity in STAT3-dependent cancer cells. The effects on STAT3 signaling were concentration dependent (FIG. 20). Although the compounds showed some toxicity on HEK cells, the toxicity was less pronounced than the effects on the signaling, strongly suggesting that the observed reduction in transcription of the marker gene was not a result of cell loss.
EXAMPLE 4
[0161] This example demonstrates the dose response of STAT3 N-domain bonding for an exemplary compound of the invention.
[0162] Recombinant STAT3 N-terminal domain titration of STND-9 was monitored by microscale thermophoresis (MST). Hexahistidine-tagged (His-tag) STAT3 N-domain was labeled with the non-covalent fluorescent dye RED-tris-NTA (RED-tris-nitrilotriacetic acid). The protein concentration was 50 nM. Fnorm was calculated as Fi/Fo, in which Fi is the fluorescence value after the laser is turned on, and Fo is the fluorescence value before the laser was turned on. As seen in FIG. 21, the apparent KD was 7.3 mM.
EXAMPLE 5
[0163] This example demonstrates the cytotoxicity of exemplary compounds of the invention.
[0164] DU145 cells were treated with compounds STND-2 (3 mM), STND-9 (3 mM), and
STND-9 (10 mM) for 3 hours (with DMSO treatment as a negative control), and nuclear fraction was isolated and used for Western blot analysis as described in Timofeeva et al.
(Proc Natl Acad Sci USA, 2013, 110(4), 1267-1272). Anti-c-Fos antibody was used at 1 : 1000 dilution. The blot was stripped and re-probed with D-Actin antibody at 1 : 1000 to demonstrate equal loading of the wells. Western blot analysis of c-Fos expression showed that the small molecule domain inhibitors of the invention effectively increase STAT3 N- domain inhibition marker c-Fos expression in prostate cancer cells.
[0165] Next, prostate cancer cells (DU145 cell line) were exposed to STND-2, STND-8, and STND-9 for 48 hours, and the number of surviving cells was quantitated using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay (Sigma-
Aldrich, St. Louis, MO). In this colorimetric assay, yellow crystals of MTT were reduced to purple crystals of formazan by metabolically active cells. Insoluble formazan crystals were dissolved using a solubilization solution, and the resulting colored solution was quantified by measuring the absorbance at 500-600 nm. The N-domain peptide inhibitor ST3H2-A2 (Timofeeva et al., Proc Natl Acad Sci USA, 2013, 110(4), 1267-1272) was used as a positive control. The effect of STAT3 N-domain inhibitors of the invention on the growth of prostate cancer is shown in FIG. 22. FIG. 23 shows that the compounds of the invention are selectively toxic to prostate tumor cells (DU145) and show very little toxicity to normal prostate epithelial cells (RWPE-1).
EXAMPLE 6
[0166] This example demonstrates the cytotoxicity of exemplary compounds of the invention.
[0167] The effect of STAT3 N-domain inhibitors STND-9, STND-25, STND-30, STND- 31, and STND-32 on the growth of pancreatic cancer cells (KPC95775 cell line) is shown in FIG. 24. Cells were exposed to compounds for 48 hours, and the number of surviving cells was quantitated using an MTT assay.
[0168] The cytotoxicity studies demonstrate that the STAT3 N-domain inhibitors of the invention are more than an order of magnitude more potent than previously described peptide inhibitors. The inhibitors of the invention show very similar in vitro effects on STAT3 signaling, and consequently can be used for both tumor growth inhibition and modulation of immune responses to tumors and infectious agents.
[0169] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[0170] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two
or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[0171] Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Claims
CLAIM(S)
1. A signal transducer and activator of transcription 3 (STAT3) protein inhibitor compound or a pharmaceutically acceptable salt thereof for use in treating a disease associated with increased activity of STAT3 protein, wherein the inhibitor compound is a phenol group-containing compound with a core structural residue selected from the group consisting of formula (la)
wherein R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, provided that the compound of formula (la) is not
formula (lb)
(lb), formula (Ic)
(Ie), wherein X1 is CH or N, X2 is a bond, CH2, or C(O), and R14 is H or F formula (If)
wherein each instance of R17 is H, alkyl,
r alkyl, and n is an integer of 1-3, formula (Ig)
Oh), wherein each of the core structural residues of formulas (la) through (Ih) is bonded to the remainder of the phenol group-containing compound, or an inhibitor compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
2. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the phenol group-containing compound has a core structural residue selected from the group consisting of:
R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, and R2 is selected from the group consisting of
wherein
R3 is heterocyclyl,
R4 is aryl, heteroaryl, or alkenyl,
R5 is haloalkyl or alkenyl,
R6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -SC alkenyl, R7 is H or alkyl,
R8 is aryl or heteroaryl, each of which is optionally substituted, R9 is alkyl or haloalkyl,
X3 is NH or O,
X4 is CH 2, C(O), or NH, and m is an integer of 1-5,
(STND-28),
(v) formula (Ie-1)
(Ie-1), wherein
X1 is CH orN,
X2 is a bond, CH2, or C(O),
R14 is H or F, and
(If-1), wherein each instance of R17 is H, alkyl,
R18 is H or alkyl, n is 1-3, and
R19 is selected from the group consisting
(Ig-1), wherein
R20 is CH 2 or CH=CH, and
3. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein R2 of formula (la-1) is selected from the group
4. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to claim 3, wherein the compound of formula (la-1) is selected from the group consisting of
,
5,
,
5. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to claim 4, wherein the compound of formula (la-1) is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
6. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the inhibitor compound is selected from the group consisting of
7. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 1-6, wherein the disease associated with increased activity of STAT3 protein is cancer.
8. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to claim 7, wherein the cancer is breast cancer, prostate cancer, pancreatic cancer, or leukemia.
9. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 1-6, wherein the disease associated with increased activity of STAT3 protein is a bacterial infection or a viral infection.
10. The STAT3 protein inhibitor compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 1-6, wherein the disease associated with increased activity of STAT3 protein is an inflammatory disease.
R1 is H, alkylcarbonyl, alkylcarboxy, amido, alkylamido, or dialkylamido, and
R3 is heterocyclyl,
R4 is aryl, heteroaryl, or alkenyl,
R5 is haloalkyl or alkenyl,
R6 is aralkyl, heteroarylalkyl, CH2C(0)alkenyl, or -S02alkenyl,
R7 is H or alkyl,
R8 is aryl or heteroaryl, each of which is optionally substituted,
R9 is alkyl or haloalkyl,
X3 is NH or O,
X4 is CH 2, C(O), or NH, and m is an integer of 1-5, or a pharmaceutically acceptable salt thereof, provided that the compound of formula (la-1) is not STND-5, STND-8, STND-9, STND-24, STND-25, STND-35, STND-36, STND-43, STND-44, or STND-45:
,
,
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound according to claim 11 or 12 and a pharmaceutically acceptable carrier.
14. A compound or a pharmaceutically acceptable salt thereof according to claim 11 or 12 for use in treating a disease associated with increased activity of signal transducer and activator of transcription 3 (STAT3) protein.
15. The compound or a pharmaceutically acceptable salt thereof for use according to claim 14, wherein the disease associated with increased activity of STAT3 protein is selected from the group consisting of cancer, a bacterial infection, a viral infection, and an inflammatory disease.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163154440P | 2021-02-26 | 2021-02-26 | |
US63/154,440 | 2021-02-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022182395A1 true WO2022182395A1 (en) | 2022-09-01 |
Family
ID=78829805
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2021/058936 WO2022182395A1 (en) | 2021-02-26 | 2021-11-11 | Small molecule inhibitors of stat3 n-terminal domain and methods of use |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022182395A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023196958A3 (en) * | 2022-04-07 | 2023-11-23 | Oncolinx Pharmaceuticals | Tumor and cancer targeting compounds |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008151037A1 (en) * | 2007-05-30 | 2008-12-11 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Peptide-based stat inhibitor |
WO2010062681A2 (en) | 2008-10-30 | 2010-06-03 | University Of South Florida | Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism |
WO2012159107A1 (en) | 2011-05-19 | 2012-11-22 | Rhode Island Hospital | Inhibition of renal fibrosis |
WO2012166891A2 (en) * | 2011-05-31 | 2012-12-06 | Algynomics Inc. | Mu-opioid receptor binding compounds |
-
2021
- 2021-11-11 WO PCT/US2021/058936 patent/WO2022182395A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008151037A1 (en) * | 2007-05-30 | 2008-12-11 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Peptide-based stat inhibitor |
WO2010062681A2 (en) | 2008-10-30 | 2010-06-03 | University Of South Florida | Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism |
WO2012159107A1 (en) | 2011-05-19 | 2012-11-22 | Rhode Island Hospital | Inhibition of renal fibrosis |
WO2012166891A2 (en) * | 2011-05-31 | 2012-12-06 | Algynomics Inc. | Mu-opioid receptor binding compounds |
Non-Patent Citations (42)
Title |
---|
"ASHP Handbook on Injectable Drugs,", 1986, pages: 622 - 630 |
"Gilman's: The Pharmacological Bases of Therapeutics,", 1990, MACK PUBLISHING COMPANY, pages: 1445 |
"Harrison's Principles of Internal Medicine", 2001, pages: 491 - 762 |
"Pharmaceutics and Pharmacy Practice", 1982, J. B. LIPPINCOTT CO., pages: 238 - 250 |
BANERJEE ET AL., INT J CANCER,, vol. 138, no. 11, 2016, pages 2570 - 2578 |
BHARADWAJ ET AL., PHARMACOL REV, vol. 72, no. 2, 2020, pages 486 - 526 |
CORVINUS ET AL., NEOPLASIA, vol. 7, no. 6, 2005, pages 545 - 555 |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 11 September 2011 (2011-09-11), XP002805642, Database accession no. 1331421-06-7 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 12 March 2008 (2008-03-12), XP002805646, Database accession no. 1007541-92-5 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 20 June 2007 (2007-06-20), XP002805647, Database accession no. 937973-42-7 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 20 June 2007 (2007-06-20), XP002805648, Database accession no. 937930-85-3 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 21 March 2010 (2010-03-21), XP002805643, Database accession no. 1212795-69-1 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 28 March 2008 (2008-03-28), XP002805645, Database accession no. 1010555-66-4 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 April 2008 (2008-04-04), XP002805644, Database accession no. 1012024-62-2 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805649, Database accession no. 937911-75-6 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805650, Database accession no. 937901-20-7 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805651, Database accession no. 937845-10-8 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805652, Database accession no. 1331726-49-8 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805653, Database accession no. 937911-66-5 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805654, Database accession no. 849040-14-8 * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002805655, Database accession no. 849040-13-7 * |
DHIR ET AL., PROSTATE, vol. 51, no. 4, 2002, pages 241 - 246 |
FILIMONOV ET AL., SAR QSAR ENVIRON RES, vol. 20, no. 7-8, 2009, pages 679 - 709 |
GARCIA ET AL., CELL GROWTH DIFFER, vol. 8, no. 12, 1997, pages 1267 - 1276 |
GKOUVERIS ET AL., JOURNAL OF CANCER THERAPY, vol. 6, 2015, pages 709 - 726 |
GKOUVERIS ET AL., JOURNAL OF CANCER THERAPY,, vol. 6, 2015, pages 709 - 726 |
GUO ET AL., AM J TRANSL RES, vol. 1, no. 3, 2009, pages 283 - 290 |
HU ET AL., MOL CELL BIOL, vol. 35, no. 19, 2015, pages 3284 - 300 |
HU WANTING: "Progress of JAK/STAT 3 and its inhibitors in the treatment of cancer", AIP CONFERENCE PROCEEDINGS AIP CONFERENCE PROCEEDINGS, 19 February 2020 (2020-02-19), pages 20045 - 1, XP055890177, Retrieved from the Internet <URL:https://aip.scitation.org/doi/pdf/10.1063/5.0000440?casa_token=IlXRJMItsoQAAAAA:PNkP49H9aVBbFJW0Syp6fka2ZnyXwrv7zn2DrP4Es0IPuMM2MLlLRe11l1B98bKc5zWPkoTARMZX> [retrieved on 20220210] * |
HUANG ET AL., GYNECOL ONCOL, vol. 79, no. 1, 2000, pages 67 - 73 |
HUYNH ET AL., NAT REV CANCER, vol. 19, no. 2, 2019, pages 82 - 96 |
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 2 - 19 |
JUDSON ET AL., J CHEM INFMODEL, vol. 60, no. 7, 2020, pages 3336 - 3341 |
MATSUYAMA ET AL., CELL DEATH DIFFER, vol. 27, no. 12, 9 October 2020 (2020-10-09), pages 3209 - 3225 |
MORA ET AL., CANCER RES, vol. 62, no. 22, 2002, pages 6659 - 6666 |
PATEL ET AL., SCIENTIFIC DATA, vol. 7, no. 384, 11 November 2020 (2020-11-11), pages 1 - 14 |
SCHAEFER ET AL., ONCOGENE, vol. 21, no. 13, 2002, pages 2058 - 2065 |
TIMOFEEVA ET AL., ACS CHEM BIOL, vol. 2, no. 12, 2007, pages 799 - 809 |
TIMOFEEVA ET AL., PROC NATL ACAD SCI USA, vol. 110, no. 4, 2013, pages 1267 - 1272 |
WATSON ET AL., BR J CANCER, vol. 71, no. 4, 1995, pages 840 - 844 |
WEI ET AL., ONCOGENE, vol. 22, no. 3, 2003, pages 319 - 329 |
YUE ET AL., EXPERT OPINION INVESTIG DRUGS,, vol. 18, no. 1, 2009, pages 45 - 56 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023196958A3 (en) * | 2022-04-07 | 2023-11-23 | Oncolinx Pharmaceuticals | Tumor and cancer targeting compounds |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW202014408A (en) | Compounds and compositions for treating conditions associated with sting activity | |
CN112823151A (en) | Compounds and compositions for treating diseases associated with STING activity | |
SA518400704B1 (en) | Crystalline forms of a triazolopyrimidine compound | |
SA518391985B1 (en) | Modulators of 5'-Nucleotidase, ECTO and The Use Thereof | |
CA3011528A1 (en) | Cyclic dinucleotides for treating conditions associated with sting activity such as cancer | |
TW202043198A (en) | Compounds and compositions for treating conditions associated with sting activity | |
ES2824026T3 (en) | Synthetic Antibody Mimetic Compounds (SyAM) Targeting Cancer, Especially Prostate Cancer | |
KR20160125361A (en) | Var2csa-drug conjugates | |
CN113905766A (en) | Programmable polymeric pharmaceuticals | |
WO2020106736A1 (en) | Compounds and compositions for treating conditions associated with sting activity | |
KR20140000275A (en) | Bifunctional molecules with antibody-recruiting and entry inhibitory activity against the human immunodeficiency virus | |
WO2020106741A1 (en) | Compounds and compositions for treating conditions associated with sting activity | |
WO2010013011A1 (en) | P53 tumor suppressor protein activating | |
BR112021000395A2 (en) | DIMMERIC IMMUNOMODULATING COMPOUNDS AGAINST CEREBLON-BASED MECHANISMS | |
US11767298B2 (en) | Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase | |
WO2019122202A1 (en) | Sting inhibitors | |
WO2022182395A1 (en) | Small molecule inhibitors of stat3 n-terminal domain and methods of use | |
JP2024502474A (en) | Urea-bearing heterobicyclic compounds or analogs and compositions thereof for treating conditions associated with STING activity | |
JP2021533183A (en) | Compounds, compositions, methods and uses for the treatment of cancer and immune disorders | |
US10000469B2 (en) | Heat shock protein 70 (hsp-70) receptor ligands | |
JP2020529988A (en) | Compounds and their use for the prevention and treatment of medical disorders | |
US10538500B2 (en) | Tricyclic prodrugs | |
TW202334084A (en) | Compounds and compositions for treating conditions associated with sting activity | |
US20240083879A1 (en) | Oxalamide compounds and compositions for treating conditions associated with sting activity | |
WO2021163467A1 (en) | Linking amino acid sequences, manufacturing method thereof, and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21823700 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21823700 Country of ref document: EP Kind code of ref document: A1 |