CN113999281A - 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 - Google Patents
平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 Download PDFInfo
- Publication number
- CN113999281A CN113999281A CN202111210158.8A CN202111210158A CN113999281A CN 113999281 A CN113999281 A CN 113999281A CN 202111210158 A CN202111210158 A CN 202111210158A CN 113999281 A CN113999281 A CN 113999281A
- Authority
- CN
- China
- Prior art keywords
- improving
- compound
- pain
- chronic
- improvement
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108091006527 nucleoside transporters Proteins 0.000 title claims abstract description 35
- 102000019055 Nucleoside Transport Proteins Human genes 0.000 title claims abstract description 24
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims abstract description 22
- 229960005305 adenosine Drugs 0.000 claims abstract description 22
- 208000002193 Pain Diseases 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 13
- 230000011664 signaling Effects 0.000 claims abstract description 12
- 208000028867 ischemia Diseases 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000004224 protection Effects 0.000 claims abstract description 7
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 6
- 230000002141 anti-parasite Effects 0.000 claims abstract description 5
- 230000001684 chronic effect Effects 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 206010003119 arrhythmia Diseases 0.000 claims description 5
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 4
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 4
- 206010020751 Hypersensitivity Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010040047 Sepsis Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 230000007815 allergy Effects 0.000 claims description 4
- 230000006793 arrhythmia Effects 0.000 claims description 4
- 201000001881 impotence Diseases 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 230000003908 liver function Effects 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 208000023504 respiratory system disease Diseases 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 208000007056 sickle cell anemia Diseases 0.000 claims description 4
- 208000000094 Chronic Pain Diseases 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000005298 acute pain Diseases 0.000 claims description 3
- 239000003146 anticoagulant agent Substances 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 239000000082 organ preservation Substances 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 206010065390 Inflammatory pain Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 2
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 229940125681 anticonvulsant agent Drugs 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 230000005961 cardioprotection Effects 0.000 claims description 2
- 150000002678 macrocyclic compounds Chemical class 0.000 claims description 2
- 230000004112 neuroprotection Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 208000019116 sleep disease Diseases 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 210000000278 spinal cord Anatomy 0.000 claims 1
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 230000006872 improvement Effects 0.000 description 48
- 239000002777 nucleoside Substances 0.000 description 27
- 108010078791 Carrier Proteins Proteins 0.000 description 18
- 150000003833 nucleoside derivatives Chemical class 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 230000032258 transport Effects 0.000 description 15
- 101000822020 Homo sapiens Equilibrative nucleoside transporter 1 Proteins 0.000 description 14
- 102100021469 Equilibrative nucleoside transporter 1 Human genes 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- DYCJFJRCWPVDHY-LSCFUAHRSA-N NBMPR Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(SCC=3C=CC(=CC=3)[N+]([O-])=O)=C2N=C1 DYCJFJRCWPVDHY-LSCFUAHRSA-N 0.000 description 11
- 102000037831 nucleoside transporters Human genes 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 125000003835 nucleoside group Chemical group 0.000 description 10
- 101000822017 Homo sapiens Equilibrative nucleoside transporter 2 Proteins 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 102100021468 Equilibrative nucleoside transporter 2 Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 210000000170 cell membrane Anatomy 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000002212 purine nucleoside Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- -1 small molecule compounds Chemical class 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- 206010013774 Dry eye Diseases 0.000 description 3
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000005061 intracellular organelle Anatomy 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 3
- 239000002718 pyrimidine nucleoside Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- 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 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 108050000203 Adenosine receptors Proteins 0.000 description 2
- 102000009346 Adenosine receptors Human genes 0.000 description 2
- 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 2
- 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 2
- 241000282412 Homo Species 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- 206010063897 Renal ischaemia Diseases 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 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 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 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 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 239000005549 deoxyribonucleoside Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical class O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- 101001064206 Arabidopsis thaliana Equilibrative nucleotide transporter 1 Proteins 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 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
- 102100021472 Equilibrative nucleoside transporter 3 Human genes 0.000 description 1
- 102000018428 Equilibrative nucleoside transporters Human genes 0.000 description 1
- 108050007554 Equilibrative nucleoside transporters Proteins 0.000 description 1
- 101000822041 Homo sapiens Equilibrative nucleoside transporter 3 Proteins 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- SCIFESDRCALIIM-VIFPVBQESA-N N-methyl-L-phenylalanine Chemical group C[NH2+][C@H](C([O-])=O)CC1=CC=CC=C1 SCIFESDRCALIIM-VIFPVBQESA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- 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
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 150000003838 adenosines Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 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
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 102000045714 human SLC29A1 Human genes 0.000 description 1
- 102000045693 human SLC29A2 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 150000002500 ions Chemical class 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
- 150000002611 lead compounds Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000009061 membrane transport Effects 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 1
- 230000004007 neuromodulation Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000009057 passive transport Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical group N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 229960003962 trifluridine Drugs 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
- 210000003606 umbilical vein Anatomy 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Urology & Nephrology (AREA)
- Tropical Medicine & Parasitology (AREA)
Abstract
本申请涉及平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途。本申请提供了式(I)的化合物，
Description
本申请是申请日为2017年2月3日，申请号为201780010178.6，发明名称为“平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途”的申请的分案申请。
相关申请
本申请根据35 U.S.C.§119(e)要求于2016年2月4日提交的美国临时申请第62/291,428号的权益，该申请通过引用以其整体并入本文。
发明领域
本发明整体上涉及小分子化合物，且更具体地涉及这种化合物用于抑制人平衡型核苷转运蛋白1(ENT1)的用途。
背景信息
转运蛋白参与各种分子进入和/或通过细胞的细胞摄入。载体介导的转运系统使用通常通过多个跨膜结构域锚定到细胞膜的蛋白并通过经由主动或被动机制转运它们的底物起作用。载体介导的转运系统参与许多重要的营养物诸如维生素、糖和氨基酸的主动或非主动的易化转运。载体介导的转运蛋白还存在于器官诸如肝和肾中，其中蛋白参与循环化合物的排泄或重吸收。极性或亲水性化合物通常不良地扩散跨过构成细胞膜的脂双层。对于许多小分子(例如氨基酸、二肽和三肽、单糖、核苷和水溶性维生素)，存在特异性载体介导的转运载体用于主动转运溶质分子跨过生物膜。
哺乳动物细胞摄入或释放生理核苷和许多其合成类似物主要通过被称为核苷转运蛋白(nucleoside transporter)的特异性载体介导的转运蛋白的方式发生。核苷转运蛋白已经被分成两类：(i)平衡型(易化扩散)和(ii)集中型(继发性主动)钠依赖型。具有类似的宽底物特异性的两种平衡型转运系统已经被鉴定并分别基于其对由硝基苄基硫代肌苷(NBMPR，1)的抑制敏感或不敏感命名为es(平衡型敏感型)和ei(平衡型不敏感性)转运蛋白。
核苷渗透跨过细胞膜需要特异性转运蛋白。在核苷转运蛋白家族中，平衡型核苷转运蛋白(ENT)是最广泛表达的，并且在人类中已经鉴定了4 种人ENT：hENT-1、hENT-2、hENT-3和hENT-4。最彻底表征的是hENT-1 和hENT-2，其是细胞表面蛋白且对于嘌呤和嘧啶核苷具有广泛的选择性。它们可以通过其对由硝基苄基硫代肌苷(NBMPR)的抑制的敏感性而彼此区分。ENT1被纳摩尔浓度的NBMPR有力地抑制，并以此也被称为NBMPR 敏感的平衡型核苷转运蛋白。ENT2对纳摩尔浓度的NBMPR不敏感，但可以被更高(微摩尔)浓度的NBMPR抑制，并因此也被称为NBMPR不敏感的平衡型核苷转运蛋白(iENTP)(参见Griffith等人,Biochim.Bioph.Acta 1286:153-181(1986))。
人平衡型核苷转运蛋白1(ENT1)由SLC29a1基因编码。该基因是平衡型核苷转运蛋白家族的成员。该基因编码定位于质膜和线粒体膜并介导核苷从周围介质的细胞摄入的跨膜糖蛋白。蛋白被分类为对由硝基苄基硫代肌苷(NBMPR)的抑制敏感的平衡型(如与集中型相对)转运蛋白。需要核苷转运蛋白用于缺乏从头核苷合成途径的细胞中的核苷酸合成，并且核苷转运蛋白对于摄入细胞毒性核苷用于癌症和病毒化学疗法也是必要的。
腺苷是内源性嘌呤核苷，其尤其在病理生理条件诸如缺血、炎症和疼痛中释放。在这些条件下，它起重要的神经和免疫调节作用。腺苷施用是人类中各种疼痛调节的镇痛药。由于腺苷的半衰期短和由其施用引起的副作用，人们对找到加强内源性腺苷的作用的方法有相当大的兴趣。抑制 ENT1阻断腺苷摄入进入细胞并且可以增强其有益效果。
发明概述
本申请提供了以下内容：
1).一种化合物，选自由以下中的一种组成的组：
式I(JW95,Rapadocin)
2).一种抑制人类平衡型核苷转运蛋白1(ENT1)的方法，包括向有相应需要的受试者施用有效量的1)的化合物，从而抑制ENT1。
3).一种增加腺苷信号传导的方法，包括向有相应需要的受试者施用有效量的1)的化合物，从而增加腺苷信号传导。
4).一种用于增加腺苷信号传导的方法，包括向有相应需要的受试者施用有效量的1)的化合物，其中施用1)的化合物导致选自由以下组成的组的效果中的一个或更多个：抗病毒活性增加、抗寄生虫活性增加、酒精耐受性增加、疼痛减少、保护免于缺血、减轻癫痫发作严重性、减少勃起功能障碍、改善肝功能、改善呼吸系统紊乱、改善脓毒症、改善血栓形成、改善高血压、改善炎性紊乱、改善过敏症、改善心脏缺血、改善心律不齐、改善帕金森病、改善慢性心力衰竭、改善类风湿性关节炎、改善干眼病、改善慢性斑块型银屑病、改善慢性神经性疼痛和改善镰刀细胞病。
5).一种化合物，所述化合物具有以下结构：
R1：
单独地或组合地，R2-R4：H甲基，乙基，丙基，异丙基，苯基，
OH，NH2，SH，CN，
单独地或组合地，R5-R6：甲基，乙基，丙基，异丙基，苯基，
OH，NH2，SH，CN，
R9＝OH，NH2，SH，CN，H；
R10＝OH，NH2，SH，CN，H.
R11-14＝H或Me.
R15＝OH，NH2，SH，CN，H；
R16＝OH，NH2，SH，CN，H.
携带R15和R16的碳之间的键可以是单键或处于E或Z构型的双键
其中残基1-4可以是以下中列出的任何氨基酸构建单元或其修饰版本
6).一种抑制人类平衡型核苷转运蛋白1(ENT1)的方法，包括向有相应需要的受试者施用有效量的5)的化合物，从而抑制ENT1。
7).一种增加腺苷信号传导的方法，包括向有相应需要的受试者施用有效量的5)的化合物，从而增加腺苷信号传导。
8).一种用于增加腺苷信号传导的方法，包括向有相应需要的受试者施用有效量的5)的化合物，其中使用5)的化合物导致选自由以下组成的组的效果中的一个或更多个：抗病毒活性增加、抗寄生虫活性增加、酒精耐受性增加、疼痛减少、保护免于缺血、减轻癫痫发作严重性、减少勃起功能障碍、改善肝功能、改善呼吸系统紊乱、改善脓毒症、改善血栓形成、改善高血压、改善炎性紊乱、改善过敏症、改善心脏缺血、改善心律不齐、改善帕金森病、改善慢性心力衰竭、改善类风湿性关节炎、改善干眼病、改善慢性斑块型银屑病、改善慢性神经性疼痛和改善镰刀细胞病。
在一个实施方案中，本发明提供了包括以下的化合物：式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、XII JW95-1、 JW95-2、JW95-3、JW95-4、JW95-5、JW95-6、JW95-7、JW95-8、JW95-9、 JW95-10、JW95-11、JW95-12、JW95-13、JW95-14、JW95-15、JW95-16、 JW95-17、JW95-18、JW95-19、JW95-20、JW95-21、JW95-22、JW95-23、 JW95-24、JW95-25、95-15-1、95-15-2、95-15-3、95-15-4、95-15-5、95-15-6、 95-15-7、95-15-8、95-15-9、95-15-10、95-15-11、95-15-12、95-15-13、95-15-14、 95-15-15、95-15-16、95-15-17、95-15-18、95-15-19、95-15-20、95-15-21、 95-15-22、95-15-23、95-15-13-2、95-15-13-3、95-15-13-4、95-15-13-5、 95-15-13-6、95-15-13-7、95-15-13-8、95-15-13-9、95-15-13-10、95-15-13-11、 95-15-13-12、95-15-13-13、95-15-13-14、95-15-13-15和JW95S2生物素。化合物在本文提供的结构中说明。
本发明的另一个实施方案是提供抑制人平衡型核苷转运蛋白1(ENT1) 的方法，包括向有相应需要的受试者施用有效量的上文列出的化合物。
本发明的另一个实施方案是提供增加腺苷信号传导的方法，包括向有相应需要的受试者施用有效量的上文列出的化合物。
本发明的另一个实施方案是提供增加腺苷信号传导的方法，包括向有相应需要的受试者施用有效量的上文列出的化合物。施用上述化合物导致以下效果中的一个或更多个：抗病毒活性增加、抗寄生虫活性增加、酒精耐受性增加、疼痛减少、保护免于缺血、减轻癫痫发作严重性、减少勃起功能障碍、改善肝功能、改善呼吸系统紊乱、改善脓毒症、改善血栓形成、改善高血压、改善炎性紊乱、改善过敏症、改善心脏缺血、改善心律不齐、改善帕金森病、改善慢性心力衰竭、改善类风湿性关节炎、改善干眼病、改善慢性斑块型银屑病、改善慢性神经性疼痛和改善镰刀细胞病。
本发明的另一个实施方案是提供具有以下结构的化合物：
R1：
单独地或组合地，R2-R4：H，甲基，乙基，丙基，异丙基，苯基，
OH，NH2，SH，CN，
单独地或组合地，R5-R8：甲基，乙基，丙基，异丙基，苯基，
OH，NH2，SH，CN，
R9＝OH，NH2，SH，CN，H；
R10＝OH，NH2，SH，CN，H.
R11-14＝H或Me.
R15＝OH，NH2，SH，CN，H；
R16＝OH，NH2，SH，CN，H，
携带R15和R16的碳之间的键可以是单键或处于E或Z构型的双键
其中残基1-4可以是以下中列出的任何氨基酸构建单元或其修饰版本
本发明的另一个实施方案是在上文讨论的方法中使用上述化合物。
本发明的其他方面和优势将从以下描述和随附的权利要求变得明显。
附图简述
图1.RapADOcin通过特异性抑制hENT1抑制3H-腺苷摄入。
图2.Rapadocin抑制人脐静脉内皮细胞(HUVEC)中的3H-胸苷摄入。
图3.RapADOcin的摄入抑制被FKBP12-结合剂雷帕霉素和FK506拮抗。
图4.当被ADP活化时，5种RapADOcin抑制人血液中血小板聚集。
图5.在小鼠模型中，RapADOcin保护免受肾缺血再灌注损伤。
发明详述
本发明的其他方面和优势将从以下描述变得明显。Rapadocin式I(独特地为RapADOcin或也命名为JW95)是合成的大环小分子。Rapadocin以高效能特异性抑制人平衡型核苷转运蛋白1(hENT1或SLC29a1)。
已经通过肾缺血模型示出Rapadocin在动物中被安全地耐受。 Rapadocin是合成的大环，包括两个“结构域”—FKBD(FKBP12结合结构域 (FKBP12 binding domain))和肽结构域。FKBD可以耐受二甲氧基苯基区域的修饰，尤其是对二羟基苯基类似物。肽片段可以耐受一系列修饰，对 ENT1抑制具有不同作用。尤其是，肽片段可以耐受N-甲基苯丙氨酸残基上的几个重要的修饰。
式I的化合物在水性溶液中至高达10μM是可溶的，并且已被示出在细胞培养基(37℃，10％胎牛血清)中抵抗降解超过5天。
已经表征了两个不同家族的核苷转运蛋白(NT)：平衡型核苷转运蛋白和集中型核苷转运蛋白。“平衡型核苷转运蛋白”或“ENT”指的是通过被动转运或易化扩散将底物沿底物的浓度梯度向下易位的转运蛋白。ENT活性不需要钠离子(或其他离子)梯度并因此被称为“Na+-独立型”转运蛋白。 ENT被分类为两种亚型中的一个，基于对由硝基苄基巯基嘌呤核苷 (NBMBR)的抑制的敏感性。
已经克隆了ENT家族的4个成员，并将其命名为ENT1、ENT2、ENT3 和ENT4。所有4种转运腺苷，但关于其转运其他核苷或核碱基的能力彼此区别。ENT1是es亚型转运蛋白。编码人ENT1的示例性多核苷酸序列包括GenBank登录号U81375，且GenBank登录号AAC51103.1代表对应的氨基酸序列。ENT1在人和啮齿动物组织中无处不在地表达，尽管不同组织之间表达水平不同。已知ENT1转运宽范围的嘌呤和嘧啶核苷。
ENT2是ei亚型转运蛋白。编码人ENT2的示例性多核苷酸序列包括 GenBank登录号AF029358，且GenBank登录号AAAC39526代表对应的氨基酸序列。ENT2在宽范围的人类和啮齿动物组织中表达，包括血管内皮、心脏、脑、胎盘、胸腺、胰腺、前列腺、肾和肌肉、骨骼肌、心肌、血液、皮肤和表达ENT2的癌细胞。表达ENT2的癌细胞包括例如某些肾肿瘤细胞、乳腺肿瘤细胞、前列腺癌细胞、结肠癌细胞、胃癌细胞、白血病细胞、肺癌细胞和卵巢癌细胞。其他类型的表达ENT-2的癌细胞是本领域已知的；(参见例如Lu X等人,Journal ofExperimental Therapeutics and Oncology 2:200-212,2002,和Pennycooke M等人,Biochemical and Biophysical Research Communications 208,951-959,2001)。ENT2在骨骼肌中表现出高表达水平。ENT2也在细胞器诸如细胞核的膜中表达。已知 ENT2转运宽范围的嘌呤和嘧啶核苷以及核碱基。
预期通过Rapadocin及其类似物抑制hENT1将增加腺苷的胞外浓度，从而增加其经由腺苷受体的信号传导。已经寻求腺苷受体激动剂作为多种疾病的治疗方法。预期Rapadocin将具有与腺苷受体激动剂类似的活性。
如本文中使用的，化合物的“治疗有效量”是当被施用至个体或动物时在个体或动物中产生足够高水平的该化合物以引起ENT1转运载体的可辨别的抑制的化合物的量。施用的准确剂量和频率取决于所使用本发明的具体化合物、被治疗的具体状况、被治疗的状况的严重程度、具体患者的年龄、体重和一般身体状况以及个体可能服用的其他药物，这对于本领域熟练的施用医师是熟知的。此外，所述“治疗有效量”可以根据所治疗的患者的应答和/或根据开出本发明的化合物处方的医师的评价降低或升高。因此，上文提及的每日有效量范围仅仅是指导。本发明的化合物可以用于制造用于治疗由平衡型核苷转运蛋白ENT1活性，特别是平衡型核苷转运蛋白ENT1抑制活性介导的状况或疾病的药物。
平衡型核苷转运蛋白ENT1介导的状况或紊乱可以包括但不限于急性和慢性疼痛状况，包括炎性疼痛、神经性疼痛、癌症疼痛、心脏保护、脑保护(cerebroprotection)、创伤性脑损伤(TBI)、脊髓保护(myeloprotection)、神经保护、慢性压迫性溃疡、伤口愈合、缺血、抗惊厥、器官移植(器官保存，如心麻痹)、睡眠障碍、胰腺炎、肾小球性肾炎和抗血栓形成(抗血小板)。
“核苷转运途径”指的是实现底物跨一个或更多个生物膜转运的一个或更多个转运蛋白的系统。例如，核苷转运途径可以介导底物跨质膜、然后是底物跨细胞内细胞器的膜转运的逐步转运。负责底物跨两个生物膜的这种逐步易位的转运蛋白或核苷转运蛋白可以是相同类型的核苷转运蛋白或可以是不同类型的核苷转运蛋白。在某些实施方案中，核苷转运蛋白可以是平衡型核苷转运蛋白。在其他实施方案中，核苷转运蛋白可以是集中型核苷转运蛋白。
“转运蛋白(transport protein)”或“转运蛋白(transporter)”是在转运分子跨过膜中具有直接或间接作用的蛋白。该术语包括，例如识别底物并通过载体介导的转运蛋白或通过受体介导的转运使其进入或离开细胞的膜结合蛋白。转运蛋白可以存在于质膜或细胞内细胞器的膜上。因此，转运蛋白协助分子转运进入细胞质或进入细胞内细胞器。
术语“核苷”指的是与5-碳糖(即戊糖)共价连接的嘌呤或嘧啶碱基。当糖是核糖时，核苷是核糖核苷；当它是2-脱氧核糖时，核苷是脱氧核糖核苷。示例性核苷包括胞苷、尿苷、腺苷、鸟苷和胸苷和对应的脱氧核糖核苷，其形成构成DNA和RNA的核苷酸的基础。
如本文中使用的，术语“核苷类似物”指的是其中碱基部分、糖部分或二者已被修饰的核苷。这种类似物通常是合成的并且模拟天然核苷，使得它们可以代替细胞功能中的核苷。例如，核苷可以代替天然的对应核苷掺入到DNA或RNA中。如此掺入的某些核苷类似物可以，例如在合成期间阻止核酸链进一步延伸。许多核苷类似物具有抗病毒或抗癌性质。核苷类似物的实例包括肌苷、脱氧腺苷类似物诸如地达诺新(2',3'-双脱氧腺苷，ddI) 和阿糖腺苷(9-O-D-呋喃核糖腺嘌呤)、脱氧胞苷类似物诸如阿糖胞苷(胞嘧啶阿拉伯糖苷、恩曲他滨、拉米夫定(2',3'-双脱氧-3'-硫代胞苷，3TC)和扎西他滨(2'-3'-双脱氧胞苷，ddC))、脱氧鸟苷类似物诸如阿巴卡韦、(脱氧-) 胸苷类似物诸如司他夫定(2'-3'-二脱氢-2'-3'-双脱氧胸苷，d4T)和齐多夫定 (叠氮胸苷或AZT)和脱氧尿苷类似物诸如碘苷和三氟尿苷。
术语“药学上可接受的盐”指的是本发明的化合物的生理上和药学上可接受的盐，例如保持母体化合物的期望的生物学活性且不向其赋予不期望的毒性作用的盐。
为了制备本发明的药物组合物，将有效量的特定化合物(以碱或酸加成盐的形式)作为活性成分在紧密共混物中与至少一种药学上可接受的载体组合，所述载体可以根据期望用于施用的制剂的形式采取宽范围的形式。理想地，这些药物组合物呈适用于，优选口服施用、直肠施用、经皮施用或肠胃外施用的单位剂型。
实施例1
RapADOcin抑制核苷摄入
相对于人平衡型核苷摄入转运蛋白2(hENT2)，Rapadocin有力地且特异性抑制hENT1的核苷摄入，hENT1和hENT2是两种最主要的平衡型核苷转运蛋白(图1)。Rapadocin抑制至少7个细胞系中的核苷摄入，并预测它抑制所有人细胞系中的核苷摄入(参见例如图2和表1)。
表1 各种细胞系中的3H-胸苷摄入
Rapafucin类似物
1JW95Diol利用修饰的FKBD，其中两个甲氧基基团被羟基基团代替。
表2
表2公开了各种Rapadocin类似物的效能。
选择的Rapadocin类似物的结构如以下表示：
实施例2
人和动物模型
已经研究了两种人和动物模型来显示Rapadocin的效力(图4和5)。在几个生理条件下，腺苷被释放到血液中，在那里它可以作用于腺苷受体。正常情况下，这种腺苷(ADO)经ENT1快速地重吸收。在Rapadocin的存在下，摄入被抑制，且ADO能够产生增强的信号传导，导致几个潜在有益的生理应答。
实施例3
可以用于改进先导化合物的药代动力学/药效动力学和溶解性的另外的化合物包括以下：
实施例4
方案1
具有FKBD 8的RapADOcin的合成路线
反应条件：i)KOH,H2O/EtOH(1/20),RT,6h；ii)Pd/C(10％),H2,MeOH, RT,1.5h；iii)叔丁基2-溴乙酸酯,K2CO3,DMF/丙酮(1/2),RT,4h；iv) (+)-DIPCl,THF,-20℃至RT,5h；v)FKBD 8,苯甲酰氯,DMAP(5％),NEt3, CH2Cl2,RT,4h；vi)TFA(10％),CH2Cl2,RT,6h；vii)琥珀酸酐,DMAP(5％), CH2Cl2,RT,3h；viii)烯丙基溴,Cs2CO3,DMF,RT,2h；ix)Pd(PPh3)4(10％), N-甲基苯胺,THF,RT,6h。
实施例5
可用于改进药代动力学/药效动力学和溶解性的化合物由以下一般结构表示：
R1：
单独地或组合地，R2-R4：H，甲基，乙基，丙基，异丙基，苯基，
OH，NH2，SH，CN，
单独地或组合地，R5-R6：甲基，乙基，丙基，异丙基，苯基，
OH，NH2，SH，CN，
R9＝OH，NH2，SH，CN，H；
R10＝OH，NH2，SH，CN，H.
R11-14＝H或Me.
R15＝OH，NH2，SH，CN，H；
R16＝OH，NH2，SH，CN，H.
携带R15和R16的碳之间的键可以是单键或处于E或Z构型的双键
残基1-4可以是表3中列出的任何氨基酸构建单元或其修饰版本。
表3.效应物结构域中的残基的氨基酸构建单元
参考文献11-15描述了腺苷激动剂在治疗各种疾病中的用途。基于这些参考文献中公开的信息，本领域普通技术人员将认识到，本申请中公开的化合物可以用于治疗这些疾病。参见例如参考文献15中的表2，因为它涉及心律不齐的治疗。
尽管已经根据具体示例性实施方案和实施例描述了本发明，但是应当理解，本文公开的实施方案仅用于说明目的，并且本领域技术人员可以在不脱离如以下权利要求所述的本发明的精神和范围的情况下进行各种修改和变更。
参考文献
以下参考文献被依赖并且以其整体并入本文。
1.Passer,B.J.et al.Identification of the ENT1 AntagonistsDipyridamole and Dilazep as Amplifiers of Oncolytic Herpes Simplex Virus-1Replication. Cancer Res.70,3890–3895(2010).
2.
M.&Schiedel,A.C.Nucleoside/nucleobase transporters:drugtargets of the future？Future Med.Chem.1,303–326(2009).
3.Melendez,R.I.&Kalivas,P.W.Last call for adenosinetransporters.Nat.Neurosci.7,795–796(2004).
4.Choi,D.-S.et al.The type 1equilibrative nucleoside transporterregulates ethanol intoxication and preference.Nat.Neurosci.7,855–861 (2004).
5.Puetz,C.et al.Nitrobenzylthioinosine compounds for relief of pain.(Google Patents,2008).at<https://www.google.com/patents/US7358235>
6.Sawynok,J.in Adenosine 343–360(Springer,2013).at <http://link.springer.com/chapter/10.1007/978-1-4614-3903-5_17>
7.Bauerle,J.D.,Grenz,A.,Kim,J.-H.,Lee,H.T.&Eltzschig,H.K. AdenosineGeneration and Signaling during Acute Kidney Injury.J.Am.Soc. Nephrol.22,14–20(2011).
8.Grenz,A.et al.The Reno-Vascular A2B Adenosine Receptor Protects theKidney from Ischemia.PLoS Med.5,e137(2008).
9.Grenz,A.et al.Equilibrative nucleoside transporter 1(ENT1)regulatespostischemic blood flow during acute kidney injury in mice.J.Clin.Invest.122,693–710(2012).
10.Zimmerman,M.A.et al.Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver duringischemia and reperfusion.Hepatology 58,1766–1778(2013).
11.Mohamadnejad,M.et al.Adenosine inhibits chemotaxis and induceshepatocyte-specific genes in bone marrow mesenchymal stem cells. Hepatology51(3),963-73(2010).
12.Wen,J.et al.Adenosine signaling:good or bad in erectile function？Arterioscler Thromn Vasc Biol 32(4),845-50(2012).
13.Xu,Z.et al.ENT1 inhibition attenuates epileptic seizure severityvia regulation of glutamatergic neurotransmission.Neuromolecular Med.17(1),1-11(2015).
14.Chen,J.eta al.Adenosine receptors as drug targets-what are thechallenges？Nat Rev Drug Disc 12(4),265-86(2013).
15.Sachdeva,S.et al.Adenosine and its receptors as therapeutictargets: An overview.Saudi Pharmaceutical Journal 21,245-253(2013).
16.Griffith et al.,Biochim.Bioph.Acta 1286:153-181(1986).
17.Lu X et al.,Journal of Experimental Therapeutics and Oncology 2:200-212,2002.
18.Pennycooke M et al.,Biochemical and Biophysical ResearchCommunications 208,951-959,2001。
Claims (9)
1.一种根据如下式(I)的大环化合物：
其中残基1、残基2、残基3和残基4是可交换的且选自如下：
2.根据权利要求1所述的化合物，其中所述化合物抑制人类平衡型核苷转运蛋白1。
3.根据权利要求1所述的化合物，其中所述化合物增加腺苷信号传导。
4.根据权利要求1所述的化合物，用作药物。
5.根据权利要求3所述的化合物在制备用于增加抗病毒活性、增加抗寄生虫活性、增加酒精耐受性、减少疼痛、保护免于缺血、减轻癫痫发作严重性、减少勃起功能障碍、改善肝功能、改善呼吸系统紊乱、改善脓毒症、改善血栓形成、改善高血压、改善炎性紊乱、改善过敏症、改善心脏缺血、改善心律不齐、改善帕金森病、改善慢性心力衰竭、改善类风湿性关节炎、改善干眼病、改善慢性斑块型银屑病、改善慢性神经性疼痛或改善镰刀细胞病的药物中的用途。
6.根据权利要求1所述的化合物在制备用于保护免于缺血的药物中的用途。
7.根据权利要求1所述的化合物在制备用于治疗通过平衡型核苷转运蛋白1活性介导的状况或紊乱的药物中的用途，其中所述状况或紊乱选自由如下组成的组：急性和慢性疼痛状况。
8.根据权利要求7所述的用途，其中所述急性和慢性疼痛状况包括炎性疼痛、神经性疼痛和癌症疼痛、心脏保护、脑保护、创伤性脑损伤、脊髓保护、神经保护、慢性压迫性溃疡、伤口愈合、缺血、抗惊厥、器官移植、器官保存、睡眠障碍、胰腺炎、肾小球性肾炎和抗血栓形成的状况。
9.根据权利要求8所述的用途，其中所述器官保存为心麻痹。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662291428P | 2016-02-04 | 2016-02-04 | |
| US62/291,428 | 2016-02-04 | ||
| CN201780010178.6A CN108697701B (zh) | 2016-02-04 | 2017-02-03 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780010178.6A Division CN108697701B (zh) | 2016-02-04 | 2017-02-03 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113999281A true CN113999281A (zh) | 2022-02-01 |
Family
ID=59500022
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780010178.6A Active CN108697701B (zh) | 2016-02-04 | 2017-02-03 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
| CN202111210158.8A Pending CN113999281A (zh) | 2016-02-04 | 2017-02-03 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780010178.6A Active CN108697701B (zh) | 2016-02-04 | 2017-02-03 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US10774110B2 (zh) |
| EP (2) | EP3782636B1 (zh) |
| JP (1) | JP7022069B2 (zh) |
| CN (2) | CN108697701B (zh) |
| AU (1) | AU2017214557B2 (zh) |
| CA (1) | CA3013650A1 (zh) |
| ES (1) | ES2837484T3 (zh) |
| MX (2) | MX2018009407A (zh) |
| WO (1) | WO2017136717A1 (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11066416B2 (en) | 2016-02-04 | 2021-07-20 | The Johns Hopkins University | Rapafucin derivative compounds and methods of use thereof |
| MX2018009408A (es) * | 2016-02-04 | 2018-11-09 | Univ Johns Hopkins | Rapaglutinas, nuevos inhibidores de transportadores de glucosa (glut) y uso de los mismos. |
| CA3013650A1 (en) * | 2016-02-04 | 2017-08-10 | The Johns Hopkins University | Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof |
| TW202126323A (zh) | 2019-10-01 | 2021-07-16 | 約翰斯赫普金斯大學 | 雷帕弗辛（Ｒａｐａｆｕｃｉｎ）衍生化合物及其使用方法 |
| AU2021253634A1 (en) * | 2020-04-07 | 2022-11-03 | iTeos Belgium SA | Macrocyclic diamine derivatives as ENT inhibitors for the treatment of cancers, and combination thereof with adenosine receptor antagonists |
| WO2023059739A1 (en) * | 2021-10-06 | 2023-04-13 | iTeos Belgium SA | Macrocyclic compounds having ent1 inhibiting activity |
| WO2023056910A1 (en) * | 2021-10-06 | 2023-04-13 | iTeos Belgium SA | Processes for preparing a macrocyclic compound having ent1 inhibiting activity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1723026A (zh) * | 2002-12-09 | 2006-01-18 | 剑桥生物工艺有限公司 | 海绵核苷(2－甲氧腺苷)在治疗疼痛,特别是痛觉过敏中的用途 |
| CN108697701A (zh) * | 2016-02-04 | 2018-10-23 | 约翰霍普金斯大学 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Family Cites Families (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5100899A (en) * | 1989-06-06 | 1992-03-31 | Roy Calne | Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof |
| US5457194A (en) * | 1993-03-17 | 1995-10-10 | Abbott Laboratories | Substituted aliphatic amine-containing macrocyclic immunomodulators |
| US5798355A (en) | 1995-06-07 | 1998-08-25 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity |
| US5527907A (en) | 1993-11-19 | 1996-06-18 | Abbott Laboratories | Macrolide immunomodulators |
| US7056935B2 (en) | 1995-06-07 | 2006-06-06 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| US5696135A (en) | 1995-06-07 | 1997-12-09 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth |
| US6984635B1 (en) | 1998-02-13 | 2006-01-10 | Board Of Trustees Of The Leland Stanford Jr. University | Dimerizing agents, their production and use |
| EP1352910A1 (en) | 2002-04-10 | 2003-10-15 | Grünenthal GmbH | New analogs of nitrobenzylthioinosine |
| JP4778893B2 (ja) | 2003-04-18 | 2011-09-21 | エナンタ ファーマシューティカルズ インコーポレイテッド | キノキサリニル大環状のｃ型肝炎セリンプロテアーゼ阻害剤 |
| US20060003362A1 (en) | 2004-06-04 | 2006-01-05 | Xenoport, Inc. | ENT1 transporters expressed in cancer cells |
| GB0417852D0 (en) | 2004-08-11 | 2004-09-15 | Biotica Tech Ltd | Production of polyketides and other natural products |
| EP2368868A1 (en) | 2005-10-28 | 2011-09-28 | Praecis Pharmaceuticals Inc. | Methods for identifying compounds of interest using encoded libraries |
| US20080306098A1 (en) | 2006-11-06 | 2008-12-11 | Mutz Mitchell W | Pharmacokinetics of protease inhibitors and other drugs |
| PT2481409T (pt) | 2007-03-07 | 2018-10-18 | Abraxis Bioscience Llc | Nanopartícula que compreende rapamicina e albumina como agente anticancerígeno |
| AU2008256644B2 (en) | 2007-05-24 | 2014-07-03 | The United States Government As Represented By The Department Of Veterans Affairs | Intranuclear protein transduction through a nucleoside salvage pathway |
| WO2010004304A1 (en) | 2008-06-17 | 2010-01-14 | Biotica Technology Limited | Novel compounds and methods for their production |
| EP3287458B1 (en) | 2010-11-30 | 2022-07-13 | The Johns Hopkins University | Hybrid cyclic libraries and screening thereof |
| WO2012106702A2 (en) | 2011-02-04 | 2012-08-09 | The General Hospital Corporation | Treatment of leukemia |
| EP2607352A1 (en) | 2011-12-22 | 2013-06-26 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Pipecolate-diketoamides for treatment of psychiatric disorders |
| KR101733736B1 (ko) | 2012-01-06 | 2017-05-10 | 삼성에스디아이 주식회사 | 리튬 이차 전지용 음극 활물질, 그 제조 방법 및 이를 포함하는 리튬 이차 전지 |
| WO2014008636A1 (en) | 2012-07-11 | 2014-01-16 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as hiv integrase inhibitors |
| EP3007696B1 (en) | 2013-06-14 | 2019-10-16 | The Board of Regents of The University of Texas System | Novel allosteric inhibitors of proteasome and methods of use thereof |
| US10533016B2 (en) | 2015-01-09 | 2020-01-14 | Revolution Medicines, Inc. | Compounds that participate in cooperative binding and uses thereof |
| EP4242304A3 (en) | 2015-10-01 | 2024-02-07 | Revolution Medicines, Inc. | Methods and reagents for analyzing protein-protein interfaces |
| MX2018009408A (es) | 2016-02-04 | 2018-11-09 | Univ Johns Hopkins | Rapaglutinas, nuevos inhibidores de transportadores de glucosa (glut) y uso de los mismos. |
| US11066416B2 (en) | 2016-02-04 | 2021-07-20 | The Johns Hopkins University | Rapafucin derivative compounds and methods of use thereof |
| CN108713028B (zh) | 2016-02-04 | 2021-12-28 | 约翰霍普金斯大学 | rapafucin文库的合成和组合物 |
| JP6894449B2 (ja) | 2016-04-22 | 2021-06-30 | アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ | 癌を治療するためのマクロ環状ｍｃｌ１阻害剤 |
| WO2018045250A1 (en) | 2016-09-02 | 2018-03-08 | The Johns Hopkins University | Mif inhibitors and methods of use thereof |
| UY37900A (es) | 2017-09-26 | 2019-04-30 | Novartis Ag | Nuevos derivados de rapamicina |
-
2017
- 2017-02-03 CA CA3013650A patent/CA3013650A1/en not_active Abandoned
- 2017-02-03 JP JP2018540114A patent/JP7022069B2/ja active Active
- 2017-02-03 CN CN201780010178.6A patent/CN108697701B/zh active Active
- 2017-02-03 AU AU2017214557A patent/AU2017214557B2/en active Active
- 2017-02-03 US US16/073,746 patent/US10774110B2/en active Active
- 2017-02-03 CN CN202111210158.8A patent/CN113999281A/zh active Pending
- 2017-02-03 MX MX2018009407A patent/MX2018009407A/es unknown
- 2017-02-03 WO PCT/US2017/016494 patent/WO2017136717A1/en active Application Filing
- 2017-02-03 EP EP20198397.0A patent/EP3782636B1/en active Active
- 2017-02-03 EP EP17748270.0A patent/EP3411032B1/en active Active
- 2017-02-03 ES ES17748270T patent/ES2837484T3/es active Active
-
2018
- 2018-08-02 MX MX2021002588A patent/MX2021002588A/es unknown
-
2020
- 2020-08-26 US US17/003,940 patent/US11555054B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1723026A (zh) * | 2002-12-09 | 2006-01-18 | 剑桥生物工艺有限公司 | 海绵核苷(2－甲氧腺苷)在治疗疼痛,特别是痛觉过敏中的用途 |
| CN108697701A (zh) * | 2016-02-04 | 2018-10-23 | 约翰霍普金斯大学 | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2017214557B2 (en) | 2022-05-19 |
| EP3782636B1 (en) | 2024-05-15 |
| JP7022069B2 (ja) | 2022-02-17 |
| MX2021002588A (es) | 2021-04-19 |
| US20200392182A1 (en) | 2020-12-17 |
| CA3013650A1 (en) | 2017-08-10 |
| EP3782636A1 (en) | 2021-02-24 |
| ES2837484T3 (es) | 2021-06-30 |
| US20190031716A1 (en) | 2019-01-31 |
| AU2017214557A1 (en) | 2018-08-16 |
| JP2019508397A (ja) | 2019-03-28 |
| EP3411032B1 (en) | 2020-09-30 |
| US11555054B2 (en) | 2023-01-17 |
| EP3411032A4 (en) | 2019-08-14 |
| EP3411032A1 (en) | 2018-12-12 |
| CN108697701A (zh) | 2018-10-23 |
| MX2018009407A (es) | 2018-11-09 |
| WO2017136717A1 (en) | 2017-08-10 |
| US10774110B2 (en) | 2020-09-15 |
| CN108697701B (zh) | 2021-10-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108697701B (zh) | 平衡型核苷转运蛋白1的抑制剂Rapadocin及其用途 | |
| Balimane et al. | Involvement of multiple transporters in the oral absorption of nucleoside analogues | |
| CA2869317C (en) | 4'-azido,3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication | |
| US9085599B2 (en) | 2′allene-substituted nucleoside derivatives | |
| US8163707B2 (en) | 4′-allene-substituted nucleoside derivatives | |
| US11975016B2 (en) | 2′-substituted-N6-substituted purine nucleotides for RNA virus treatment | |
| Lin et al. | Advance of structural modification of nucleosides scaffold | |
| WO2013044030A1 (en) | 2'-chloroacetylenyl substituted nucleoside derivatives | |
| JP2007269798A (ja) | Ｂ型肝炎の治療のためのβ−Ｌ−２’−デオキシ−ヌクレオシド | |
| EP2710023A2 (en) | Purine monophosphate prodrugs for treatment of viral infections | |
| KR20110115601A (ko) | 암 및 바이러스 감염 치료용 퓨린 뉴클레오시드 모노포스페이트 프로드럭 | |
| KR20030032967A (ko) | 2'-데옥시-β-Ｌ-뉴클레오시드의 3'-프로드럭 | |
| US20160016986A1 (en) | Stabilized nucleotides for medical treatment | |
| Pastor-Anglada et al. | Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling | |
| WO2013056510A1 (zh) | 脱氧核苷与核苷组合在制备肿瘤药物中的应用 | |
| Ho et al. | The Nucleoside Transporters CNTs and ENTs | |
| IL142982A (en) | Medicaments containing ?? - l-azido - 2',3' - dideoxy - 5 - fluorocytidine derivatives for the treatment of hiv infection | |
| Yue et al. | Research Progress on hCNT3 Structure/Function and Nucleoside Anticancer Drugs | |
| Jacobson et al. | Modified nucleosides as selective modulators of adenosine receptors for therapeutic use | |
| Ivanov et al. | Kenneth A. Jacobson, Bhalchandra V. Joshi, Ben Wang, Athena Klutz, Yoonkyung Kim | |
| US20110118205A1 (en) | Anti-tumor agent comprising cytidine derivative and carboplatin | |
| TW201215395A (en) | Substituted nucleotide analogs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |