CN114209706A - 维生素d类似物用于治疗或预防病毒性肝炎的应用 - Google Patents
维生素d类似物用于治疗或预防病毒性肝炎的应用 Download PDFInfo
- Publication number
- CN114209706A CN114209706A CN202210016133.2A CN202210016133A CN114209706A CN 114209706 A CN114209706 A CN 114209706A CN 202210016133 A CN202210016133 A CN 202210016133A CN 114209706 A CN114209706 A CN 114209706A
- Authority
- CN
- China
- Prior art keywords
- compound
- hepatitis
- hydroxy
- formula
- hbsag
- 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
- 206010019799 Hepatitis viral Diseases 0.000 title claims abstract description 19
- 201000001862 viral hepatitis Diseases 0.000 title claims abstract description 19
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 title abstract description 11
- 229930003316 Vitamin D Natural products 0.000 title abstract description 6
- 235000019166 vitamin D Nutrition 0.000 title abstract description 6
- 239000011710 vitamin D Substances 0.000 title abstract description 6
- 150000003710 vitamin D derivatives Chemical class 0.000 title abstract description 6
- 229940046008 vitamin d Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 101710142246 External core antigen Proteins 0.000 claims description 41
- 239000003814 drug Substances 0.000 claims description 37
- 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 claims description 25
- 208000002672 hepatitis B Diseases 0.000 claims description 23
- 229960000980 entecavir Drugs 0.000 claims description 21
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical group 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 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 108010050904 Interferons Proteins 0.000 claims description 16
- 229940079322 interferon Drugs 0.000 claims description 16
- -1 C2-C10Alkenyl radical Chemical group 0.000 claims description 15
- 102000014150 Interferons Human genes 0.000 claims description 15
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 claims description 13
- 229960004946 tenofovir alafenamide Drugs 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229940127073 nucleoside analogue Drugs 0.000 claims description 11
- 229910052736 halogen Chemical group 0.000 claims description 9
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 claims description 9
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 8
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 230000003612 virological effect Effects 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 5
- 238000007918 intramuscular administration Methods 0.000 claims description 5
- 238000007913 intrathecal administration Methods 0.000 claims description 5
- 238000001990 intravenous administration Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002777 nucleoside Substances 0.000 claims description 5
- 230000002685 pulmonary effect Effects 0.000 claims description 5
- 238000007920 subcutaneous administration Methods 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 208000005331 Hepatitis D Diseases 0.000 claims 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 1
- 208000006454 hepatitis Diseases 0.000 abstract description 16
- 231100000283 hepatitis Toxicity 0.000 abstract description 16
- 241000700721 Hepatitis B virus Species 0.000 description 74
- 108091036055 CccDNA Proteins 0.000 description 35
- 239000003112 inhibitor Substances 0.000 description 33
- 230000005764 inhibitory process Effects 0.000 description 29
- 230000000694 effects Effects 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 19
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 229960002535 alfacalcidol Drugs 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 241000700605 Viruses Species 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 229960000987 paricalcitol Drugs 0.000 description 10
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000003446 ligand Substances 0.000 description 9
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 235000021318 Calcifediol Nutrition 0.000 description 7
- 101710132601 Capsid protein Proteins 0.000 description 7
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 7
- 229960004361 calcifediol Drugs 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 229960004556 tenofovir Drugs 0.000 description 7
- 239000000556 agonist Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000010076 replication Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 108010047761 Interferon-alpha Proteins 0.000 description 5
- 102000006992 Interferon-alpha Human genes 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 239000012228 culture supernatant Substances 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 235000005282 vitamin D3 Nutrition 0.000 description 5
- 239000011647 vitamin D3 Substances 0.000 description 5
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 5
- 229940021056 vitamin d3 Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 238000012054 celltiter-glo Methods 0.000 description 4
- 208000019425 cirrhosis of liver Diseases 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229960002061 ergocalciferol Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 235000001892 vitamin D2 Nutrition 0.000 description 4
- 239000011653 vitamin D2 Substances 0.000 description 4
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 4
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102000011931 Nucleoproteins Human genes 0.000 description 3
- 108010061100 Nucleoproteins Proteins 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 229960005084 calcitriol Drugs 0.000 description 3
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960000413 doxercalciferol Drugs 0.000 description 3
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 2
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 2
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 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
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108700024845 Hepatitis B virus P Proteins 0.000 description 2
- 208000037262 Hepatitis delta Diseases 0.000 description 2
- 241000724709 Hepatitis delta virus Species 0.000 description 2
- 241000709721 Hepatovirus A Species 0.000 description 2
- 102100034349 Integrase Human genes 0.000 description 2
- 101710084021 Large envelope protein Proteins 0.000 description 2
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 2
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 2
- 108091006611 SLC10A1 Proteins 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108010078233 Thymalfasin Proteins 0.000 description 2
- 102400000800 Thymosin alpha-1 Human genes 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- IACQCQDWSIQSRP-ZCFIWIBFSA-N [(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-[hydroxy(phosphonooxy)phosphoryl]oxyphosphinic acid Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(=O)OP(O)(=O)OP(O)(O)=O)C=NC2=C1N IACQCQDWSIQSRP-ZCFIWIBFSA-N 0.000 description 2
- 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 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 238000013473 artificial intelligence Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000005571 horizontal transmission Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 229940076155 protein modulator Drugs 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000003161 ribonuclease inhibitor Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 2
- 229960004231 thymalfasin Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000001226 triphosphate Substances 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 230000005570 vertical transmission Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- KHWCHTKSEGGWEX-RRKCRQDMSA-N 2'-deoxyadenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(O)=O)O1 KHWCHTKSEGGWEX-RRKCRQDMSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-DCHLRESJSA-N 25-Hydroxyvitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C/C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DCHLRESJSA-N 0.000 description 1
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000034534 Cotransporters Human genes 0.000 description 1
- 108020003264 Cotransporters Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 206010019670 Hepatic function abnormal Diseases 0.000 description 1
- 206010019705 Hepatic pain Diseases 0.000 description 1
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 108010074870 Histone Demethylases Proteins 0.000 description 1
- 102000008157 Histone Demethylases Human genes 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 1
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 description 1
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 1
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 1
- 101001125032 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 1 Proteins 0.000 description 1
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 201000002980 Hyperparathyroidism Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 229940124753 IL-2 agonist Drugs 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000001617 Interferon Receptors Human genes 0.000 description 1
- 108010054267 Interferon Receptors Proteins 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 102100039350 Interferon alpha-7 Human genes 0.000 description 1
- 102000007438 Interferon alpha-beta Receptor Human genes 0.000 description 1
- 108010086140 Interferon alpha-beta Receptor Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 101150069255 KLRC1 gene Proteins 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 1
- 102000018170 Lymphotoxin beta Receptor Human genes 0.000 description 1
- 108010091221 Lymphotoxin beta Receptor Proteins 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 description 1
- 101100404845 Macaca mulatta NKG2A gene Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000029725 Metabolic bone disease 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
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 102100022682 NKG2-A/NKG2-B type II integral membrane protein Human genes 0.000 description 1
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 1
- 102100038082 Natural killer cell receptor 2B4 Human genes 0.000 description 1
- 101710141230 Natural killer cell receptor 2B4 Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 101150083031 Nod2 gene Proteins 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 102100029424 Nucleotide-binding oligomerization domain-containing protein 1 Human genes 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
- 208000001132 Osteoporosis Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000009658 Peptidylprolyl Isomerase Human genes 0.000 description 1
- 108010020062 Peptidylprolyl Isomerase Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 101150036449 SIRPA gene Proteins 0.000 description 1
- 206010039984 Senile osteoporosis Diseases 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 102100021988 Sodium/bile acid cotransporter Human genes 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101000919178 Streptomyces griseolus Vitamin D3 dihydroxylase Proteins 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 238000010459 TALEN Methods 0.000 description 1
- 101150038509 TLR9 gene Proteins 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 108010046075 Thymosin Proteins 0.000 description 1
- 102000007501 Thymosin Human genes 0.000 description 1
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 108010087302 Viral Structural Proteins Proteins 0.000 description 1
- 229940118555 Viral entry inhibitor Drugs 0.000 description 1
- 108010017070 Zinc Finger Nucleases Proteins 0.000 description 1
- ZTWBIZVVFNIRSF-HAFWLYHUSA-N [(1s,3s,5s)-3-(2-amino-6-oxo-3h-purin-9-yl)-5-hydroxy-2-methylidenecyclopentyl] [hydroxy(phosphonooxy)phosphoryl] hydrogen phosphate Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](OP(O)(=O)OP(O)(=O)OP(O)(O)=O)C1=C ZTWBIZVVFNIRSF-HAFWLYHUSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000037628 acute hepatitis B virus infection Diseases 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001185 bone marrow 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
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 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
- 159000000007 calcium salts Chemical class 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000000134 cyclophilin inhibitor Substances 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 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
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229940036998 hypertonic sodium chloride Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002480 immunoprotective effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 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
- 239000003394 isomerase inhibitor Substances 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
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 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
- 230000000503 lectinlike effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 108010078070 scavenger receptors Proteins 0.000 description 1
- 102000014452 scavenger receptors Human genes 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229940075439 smac mimetic Drugs 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 229940104261 taurate Drugs 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-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
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 229940044655 toll-like receptor 9 agonist Drugs 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
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Abstract
Description
本申请要求享有于2021年1月10日向中国国家知识产权局提交的,专利申请号为202110027380.8,名称为“维生素D类似物用于治疗或预防病毒性肝炎的应用”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及抗病毒药物技术领域,具体地,涉及一种用于治疗或预防病毒性肝炎的药物组合物及其应用。
背景技术
人乙型肝炎病毒(HBV)感染是世界范围内的重要公共健康问题。急性乙肝病毒感染后,仍有8%左右发展为慢性乙型肝炎感染,持续性HBV感染将导致肝硬化,甚至肝癌。尽管随着乙肝疫苗的大范围普及,新乙肝感染率得到有效控制,但乙肝病毒携带者人口基数大,防治乙肝成为公共健康问题的重中之重。乙肝传播途径主要通过垂直传播与水平传播。垂直传播是指母婴传播;水平传播主要通过血液和体液传播。
乙型肝炎的治疗也是一个长期的过程,治疗目标就是最大限度地抑制或消除HBV,减轻肝细胞炎症坏死及肝纤维素化,延缓和阻止疾病进展,减少和防止肝脏失代偿、肝硬化、肝细胞性肝癌及其并发症的发生,从而改善生活质量和延长存活时间。
目前市场上有很多乙型肝炎治疗药物,主要通过使用干扰素或者核苷类似物进行抗病毒治疗。对于干扰素而言,重组DNA白细胞干扰素(IFN-α)可抑制HBV的复制。但是干扰素在治疗乙肝时,往往伴随着较强的不良反应,包括骨髓抑制,影响甲状腺功能和抑郁等。
核苷类似物主要通过抑制HBV复制过程中的逆转录酶活性从而抑制HBV产生,临床可用药物包括以下类别:拉米夫定、泛昔洛韦、如阿昔洛韦、阿德福韦、恩替卡韦、替诺福韦、膦甲酸钠等,这些药物均有一定抑制HBV效果。
这些逆转录酶抑制剂虽然可以有效降低HBV DNA水平,使患者控制乙肝病毒水平,但是由于其作用靶点为RNA逆转录为DNA的过程,对于HBV cccDNA和HBsAg的清除无直接作用。因此核苷类似物单药治疗发生HBsAg血清学转化的概率极低,并不能真正治愈乙肝,患者需要长期甚至终身服用药物。
在长期服用上述药物的条件下,所产生的耐药性、巨额的医药费用、药物严重的副作用等问题对于乙肝病人来说是沉重的负担。关键是,目前仍然没有一种药物能够完全清除病毒达到功能性治愈乙肝。因此,本领域迫切需要提供一种新的治疗乙型肝炎、能够清除HBsAg、HBeAg达到功能性治愈的药物。
发明内容
本发明通过人工智能系统,基于多个乙肝治疗靶点和大数据分析,筛选出了具有乙肝治疗效果的通式1的化合物,进一步通过生物学实验的验证,获得了具有清除HBsAg和HBeAg效果的通式1的化合物,有望功能性治愈乙肝,清除乙肝病毒。
在一个实施方式中,本发明提供了通式1的化合物,其衍生物或其药学上可接受的盐在制备用于治疗或预防病毒性肝炎的药物中的用途:
其中,R1和R2为氢、羟基、C1-C10烷氧基或C1-10烷酰氧基;R3为氢或任选羟基取代的C1-C10烷氧基;R4和R5各自为H或与其相连的R2处的碳原子一起构成碳碳双键;
R选自C1-C10烷基、C2-C10烯基、C2-C10炔基、C1-C10烷氧基、羟基和/或卤素取代的C1-C10烷基、羟基和/或卤素取代的C1-C10烷氧基、羟基和/或卤素取代的C2-C10烯基、羟基和/或卤素取代的C2-C10炔基和C1-10烷酰氧基。
在一个实施方式中,所述R选自具有如下通式1-1的部分:
通式1-1
其中,*表示与相邻原子的连接位点,R1表示氢或羟基,R2和R3各自选自任选卤素取代的C1-C5烷基,或它们一起表示-(CH2)m-环状部分,其中m是2至5的整数,R4选自氢、羟基或C1-C5烷基,R5选自氢或C1-C5烷基,R6和R7各自选自氢、羟基或C1-C5烷基,或R6和R7连同其各自连接的碳一起形成碳-碳双键或碳碳叁键,其中n为1至5的整数。
通式1-1的基团进一步可选自如下式a至式d:
在一个优选的实施方式中,所述通式1的化合物选自下列化合物:
优选化合物9(帕立骨化醇,HD009)、化合物18(阿法骨化醇,HD125)和化合物3(骨化二醇,HD135):
根据本发明的另一实施方案,本发明还提供一种所述通式1的化合物或其药学上可接受的盐的衍生物,所述衍生物为氘代化合物或其他同位素标记化合物,优选为氘代化合物。
在一个优选的实施方式中,其中所述通式1的衍生物为其氘代化合物或其他同位素标记,优选为氘代化合物。例如化合物9-2。
在一个优选的实施方式中,本发明提供了式1的化合物、其衍生物或其药学上可接受的盐在制备用于降低或清除HBsAg和/或HBeAg的药物中的用途。
所述药学上可接受的盐包括但不限于:醋酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、乳酸盐、苹果酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、硫氰酸盐、甲苯磺酸盐、十一烷酸盐、钠盐、钙盐、钾盐、铵盐、四乙铵盐、甲铵盐、二甲铵盐和乙醇胺盐。
在另一个优选的实施方式中,所述化合物被氘取代或其他同位素标记。其中,氘取代的化合物能够在保持原化合物的活性的同时,提高该化合物的半衰期。
在一个优选的实施方式中,所述病毒性肝炎为乙型肝炎或丁型肝炎。
在一个优选的实施方式中,所述药物能够降低乙型肝炎病毒(HBV)载量、HBsAg和/或HBeAg水平。特别地,所述药物能够降低HBsAg和/或HBeAg水平。
本发明还提供了上述式1的化合物、其衍生物或其药学上可接受的盐,以及一种或多种另外的治疗剂或预防剂在制备用于降低或清除HBsAg和/或HBeAg的药物中的用途。在一个优选的实施方式中,所述另外的治疗剂或预防剂选自TAF、干扰素、PEG化的干扰素、式A所示的化合物或者核苷类似物,
优选地,所述核苷类似物选自恩替卡韦、富马酸替诺福韦二吡呋酯和替诺福韦艾拉酚胺。
在一个优选的实施方式中,所述药物经配制通过选自以下的途径施用:口服、直肠、经鼻、经肺、局部、口腔和舌下、阴道、肠胃外、皮下、肌肉内、静脉内、皮内、鞘内和硬膜外,优选口服施用,更优选为片剂或胶囊的形式。
本发明还提供一种药物组合物,其包含上述的通式1的化合物、其衍生物或其药学上可接受的盐。
本发明还提供了一种用于治疗或预防病毒性肝炎的药物组合物,其包含治疗有效量的通式1的化合物、其衍生物或其药学上可接受的盐,以及任选的一种或多种另外的治疗剂或预防剂,以及药学上可接受的载体。
根据本发明的优选技术方案,所述通式1的化合物选自:
进一步优选化合物9(帕立骨化醇,HD009)、化合物18(阿法骨化醇,HD125)和化合物3(骨化二醇、HD135):
更优选地,所述另外的治疗剂或预防剂选自干扰素、PEG化的干扰素、式A所示的化合物或者核苷类似物中的至少一种。
在一个优选实施方式中,所述病毒性肝炎为乙型肝炎。在一个优选实施方式中,所述药物能够降低乙型肝炎病毒(HBV)载量、HBsAg和/或HBeAg水平。
在一个优选实施方式中,所述通式1的化合物为已知药物帕立骨化醇(化合物9)、阿法骨化醇(化合物18)或骨化二醇(化合物3)。
帕立骨化醇是一种人工合成的具有生物活性的维生素D类似物,是一种类似合成维生素D2的药品,用于防止和治疗血液透析的慢性肾衰患者出现的甲状旁腺功能亢进症。阿法骨化醇,其只需通过肝脏转化后即可得到骨化三醇(1,25-二羟基维生素D3),不同于其他维生素D3,需要先经过肝脏转化成为25-羟基维生素D3,再经过肾脏转化为1,25-二羟基维生素D3。骨化二醇是人体内维生素D3(VD3)在肝脏的VD3羟化酶的作用下转化而来,对空气、热、光敏感,易溶于乙醇等极性有机溶剂,不溶于水。Chemicalbook由美国Upjohn公司上世纪八十年代开发上市,用于治疗老年人骨质疏松症等各种慢性骨紊乱,以及与慢性肾衰竭有关的代谢性骨病。目前尚无所述三种物质用于乙肝治疗的任何报道。
在一个优选的实施方式中,所述另外的治疗剂或预防剂选自TAF、干扰素、PEG化的干扰素、式A所示的化合物或者核苷类似物,
优选地,所述核苷类似物选自恩替卡韦、富马酸替诺福韦二吡呋酯和替诺福韦艾拉酚胺。
在一个优选的实施方式中,本发明的药物选自以下制剂形式:口服、直肠、经鼻、经肺、局部、口腔和舌下、阴道、肠胃外、皮下、肌肉内、静脉内、皮内、鞘内和硬膜外,优选口服制剂,更优选为片剂或胶囊的形式。
本申请的发明人通过人工智能系统分析和研究了药物结构和靶点的大数据后意外发现这一系列化合物具有治疗乙肝的潜在活性。在经过了一系列生物学实验验证后,获得了通式1的化合物的乙肝治疗用途。
有益效果
1.将通式1的化合物或其药学上可接受的盐应用于治疗或预防病毒性肝炎,从而提供了一种新颖的病毒性肝炎治疗选项,关键是能够同时高效清除HBsAg和HBeAg,有望达到功能性治愈乙肝的效果。
2.通式1的化合物或其药学上可接受的盐能够同时有效降低乙型肝炎病毒(HBV)载量、HBsAg和/或HBeAg水平,特别是与现有的核苷类似物药物联用的情况下,有望清除乙肝病毒,治愈乙肝,避免终身服药的痛苦。
3.作为已上市的药物,维生素D类似物,特别是帕立骨化醇、阿法骨化醇或骨化二醇或其药学上可接受的盐具有优异的临床安全性和药代动力学性质,具有较好的成药性。
4.通式1的化合物或其药学上可接受的盐能够任选地与一种或多种另外的治疗剂或预防剂进行组合,从而为后续的组合给药设计提供了广阔的思路,并具有协同增效的可能性。
附图说明
图1为根据本发明实施例的化合物9对于HBV DNA的抑制结果。
图2为根据本发明实施例的化合物9对于HBsAg的抑制结果。
图3为根据本发明实施例的化合物9对于HBeAg的抑制结果。
图4为化合物HD125(阿法骨化醇,化合物18)对HepG2-NTCP细胞的活性测试结果:(a)为对HBV DNA的抑制率曲线;(b)为对HBsAg的抑制率曲线;(c)为对HBeAg的抑制率曲线;(d)为对HepG2-NTCP细胞的毒性曲线。
图5为化合物HD131(维生素D2)对HepG2-NTCP细胞的活性测试结果:(a)为对HBVDNA的抑制率曲线;(b)为对HBsAg的抑制率曲线;(c)为对HBeAg的抑制率曲线;(d)为对HepG2-NTCP细胞的毒性曲线。
图6为化合物HD132(维生素D3)对HepG2-NTCP细胞的活性测试结果:(a)为对HBVDNA的抑制率曲线;(b)为对HBsAg的抑制率曲线;(c)为对HBeAg的抑制率曲线;(d)为对HepG2-NTCP细胞的毒性曲线。
图7为化合物HD134(度骨化醇)对HepG2-NTCP细胞的活性测试结果:(a)为对HBVDNA的抑制率曲线;(b)为对HBsAg的抑制率曲线;(c)为对HBeAg的抑制率曲线;(d)为对HepG2-NTCP细胞的毒性曲线。
图8为化合物HD135(骨化二醇)对HepG2-NTCP细胞的活性测试结果:(a)为对HBVDNA的抑制率曲线;(b)为对HBsAg的抑制率曲线;(c)为对HBeAg的抑制率曲线;(d)为对HepG2-NTCP细胞的毒性曲线。
术语定义与详细说明
取代基的定义
本文中所用的“烷基”是指具有1至10个碳原子的直链或支链脂肪族饱和烃单价基团,并且其非限制性实例包括甲基、乙基、丙基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、庚基、辛基、壬基、癸基等。
本文中所用的“羟基”是指-OH基团,其可以被保护基团保护,例如通过酯键形成烷酰氧基,例如乙酰氧基保护基团。在体内酯酶的作用下可以脱掉该保护基团,形成有活性的羟基。
本文中所用的“卤素”是指氟、氯、溴、碘中的至少一种。
本文中所用的“氨基”是指取代或未取代的-NH2基团,其可以被形成酰胺键而被保护,并在代谢过程中通过体内酶的降解而形成活性氨基发挥作用。
本文中所用的“酰胺基”是指保护氨基之后形成的带有酰胺键的基团。例如丙氨酸等氨基酸的羧基与氨基发生脱水反应之后形成的酰胺键。
本文中所用的“烷酰氧基”是指羟基经酯键保护之后形成的基团RCOO-,例如乙酰氧基,丙酰氧基、丁酰氧基等,其中R可为C1-10烷基。
本文中所用的“羧基”是指-RCOOH,R可为C1-10烷基。
病毒性肝炎
病毒性肝炎的病原学分型,目前已被公认的有甲、乙、丙、丁、戊五种肝炎病毒,分别写作HAV、HBV、HCV、HDV、HEV,除乙型肝炎病毒为DNA病毒外,其余均为RNA病毒。
乙型肝炎是由乙型肝炎病毒引起的以肝脏病变为主的一种传染病。临床上以食欲减退、恶心、上腹部不适、肝区痛、乏力为主要表现。部分患者可有黄疸发热和肝大伴有肝功能损害。有些患者可慢性化,甚至发展成肝硬化,少数可发展为肝癌。
乙型病毒性肝炎的病原为乙型肝炎病毒,缩写为HBV,乙型肝炎病毒为DNA病毒。基因组是双链、环形、不完全闭合DNA。病毒最外层是病毒的外膜或称衣膜,其内层为核心部分,核蛋白即是核心抗原(HBcAg),不能在血清中检出。HBsAg阳性者的血清在电子显微镜下可见3种颗粒,直径为22nm的圆形和丝状颗粒,还有较少的直径为42埃的球形颗粒,又称为Dane氏颗粒,是完整的HBV颗粒。
乙型肝炎的标志检测如下:①HBsAg与抗-HBs:HBsAg阳性表示HBV目前处于感染阶段,抗-HBs为免疫保护性抗体阳性示已产生对HBV的免疫力。慢性HBsAg携带者的诊断依据为无任何临床症状和体征、肝功能正常,HBsAg持续阳性6个月以上者。②HBeAg与抗-HBe:HBeAg阳性为HBV活跃复制及传染性强的指标,被检血清从HBeAg阳性转变为抗-HBe阳性表示疾病有缓解,感染性减弱。③HBcAg与抗-HBc:HBcAg阳性提示存在完整的HBV颗粒直接反应,HBV活跃复制由于检测方法复杂临床少用。抗-HBc为HBV感染的标志,抗-HBc IgM阳性提示处于感染早期,体内有病毒复制。在慢性轻度乙型肝炎和HBsAg携带者中HBsAg、HBeAg和抗-HBc三项均阳性具有高度传染性指标难以转阴。
在一个优选实施方式中,所述药物还包含一种或多种另外的治疗剂或预防剂。在一个优选实施方式中,所述另外的治疗剂或预防剂选自干扰素或者核苷类似物。在一个优选实施方式中,所述核苷类似物选自恩替卡韦、富马酸替诺福韦二吡呋酯和替诺福韦艾拉酚胺。
另外的治疗剂或预防剂
在一些实施方式中,所述另外的治疗剂或预防剂选自恩替卡韦(ETV)、富马酸替诺福韦二吡呋酯和替诺福韦艾拉酚胺中的一种或多种,例如选自恩替卡韦、富马酸替诺福韦二吡呋酯和替诺福韦艾拉酚胺中的一种或选自恩替卡韦、富马酸替诺福韦二吡呋酯和替诺福韦艾拉酚胺中的至少两种。
恩替卡韦(Entecavir)的化学名为2-氨基-1,9-二氢-9-[(1S,3R,4S)-4-羟基-3-(羟甲基)-2-亚甲基环戊烷]-6H-嘌呤-6-酮,其结构式如下:
美国专利US5206244公开了恩替卡韦及其治疗乙肝病毒的用途;WO9809964中公开了新的恩替卡韦合成方法;WO0164421公开了低剂量的恩替卡韦固体制剂。
恩替卡韦是一种高效的抗病毒剂,由美国施贵宝公司在20世纪90年代研发,具有较强的抗HBV作用。它能够通过磷酸化成为具有活性的三磷酸盐,三磷酸盐在细胞内的半衰期为15h。通过与HBV多聚酶的天然底物三磷酸脱氧鸟嘌呤核苷竞争,恩替卡韦三磷酸盐能抑制病毒多聚酶(逆转录酶)的所有三种活性:(1)HBV多聚酶的启动;(2)前基因组mRNA逆转录负链的形成;(3)HBV DNA正链的合成。
富马酸替诺福韦二吡呋酯(英文名:Tenofovir disoproxil fumarate,TDF;化学名为(R)-[[2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]膦酸二异丙氧羰基甲酯富马酸盐)是替诺福韦的酯类前体,属于新型核苷酸类逆转录酶抑制剂,具有抑制HBV病毒活性。
TDF是美国吉利德公司继阿德福韦酯后成功开发的另一个新型开环膦酸核苷类化合物于2001年10月首次在美国上市,目前已经在欧洲、澳大利亚和加拿大等国家上市。
TDF在体内可通过竞争性地结合于天然脱氧核糖底物来抑制病毒聚合酶,并通过插入DNA中终止DNA链的合成。其主要作用机制为口服后水解为替诺福韦,替诺福韦被细胞激酶磷酸化,生成具有药理活性的代谢产物替诺福韦二磷酸,后者与5’-三磷酸脱氧腺苷酸竞争,参与病毒DNA的合成,进入病毒DNA后,由于缺乏3’-OH基团,导致DNA延长受阻,进而阻断病毒的复制。临床应用表明,TDF具有显著的抗HBV病毒疗效,并且毒副作用较小,因而具有较大的临床应用前景。
替诺福韦艾拉酚胺(Tenofovir Alafenamide),是由美国吉利德科学公司开发的一种新核苷类逆转录酶抑制剂(NRTI)替诺福韦(Tenofovir)的前体药物。与上一代的抗乙肝类似药物替诺福韦二吡呋酯TDF相比,替诺福韦艾拉酚胺的抗病毒活性为其10倍,在血浆中的稳定性为其200倍,半衰期较其提高了225倍。与TDF相比,替诺福韦艾拉酚胺只需要十分之一的TDF给药剂量,即可实现与TDF相同的抗病毒疗效。因此替诺福韦艾拉酚胺用于乙型肝炎病毒(HBV)感染的预防或/和治疗,具有更好的疗效、更高的安全性和更低的耐药性。
除了上述活性药物外,本文所述的药物或药物组合物还可任选地包含一种或多种另外的用于治疗HBV的其他药物,其例如但不限于3-双加氧酶(IDO)抑制剂,靶向病毒mRNA的反义寡核苷酸,载脂蛋白A1调节剂,精氨酸酶抑制剂,B-和T-淋巴细胞减毒剂抑制剂,Bruton酪氨酸激酶(BTK)抑制剂,CCR2趋化因子拮抗剂,CD137抑制剂,CD160抑制剂,CD305抑制剂,CD4激动剂和调节剂,靶向HBcAg的化合物,靶向乙型肝炎核心抗原(HBcAg)的化合物,共价闭合环状DNA(cccDNA)抑制剂,亲环蛋白抑制剂,细胞因子,细胞毒性T淋巴细胞相关蛋白4(ipi4)抑制剂,DNA聚合酶抑制剂,核酸内切酶调节剂,表观遗传修饰剂,法尼醇X受体激动剂,基因修饰剂或编辑物,HBsAg抑制剂,HBsAg分泌或组装抑制剂,HBV抗体,HBV DNA聚合酶抑制剂,HBV复制抑制剂,HBV RNA酶抑制剂,HBV疫苗,HBV病毒进入抑制剂,HBx抑制剂,乙型肝炎大包膜蛋白调节剂,乙型肝炎大包膜蛋白刺激剂,乙型肝炎结构蛋白调节剂,乙型肝炎表面抗原(HBsAg)抑制剂,乙型肝炎表面抗原(HBsAg)分泌或组装抑制剂,乙型肝炎病毒E抗原抑制剂,乙型肝炎病毒复制抑制剂,肝炎病毒结构蛋白抑制剂,HIV-1逆转录酶抑制剂,透明质酸酶抑制剂,IAP抑制剂,IL-2激动剂,IL-7激动剂,免疫球蛋白激动剂,免疫球蛋白G调节剂,免疫调节剂,吲哚胺-2,核糖核苷酸还原酶抑制剂,干扰素激动剂,干扰素α1配体,干扰素α2配体,干扰素α5配体调节剂,干扰素α配体,干扰素α配体调节剂,干扰素α受体配体,干扰素β配体,干扰素配体,干扰素受体调节剂,白介素-2配体,ipi4抑制剂,赖氨酸脱甲酶抑制剂,组蛋白脱甲酶抑制剂,KDM5抑制剂,KDM1抑制剂,杀伤细胞凝集素样受体亚家族G成员1抑制剂,淋巴细胞活化基因3抑制剂,淋巴毒素β受体激活剂,微RNA(miRNA)基因治疗剂,Axl调节剂,B7-H3调节剂,B7-H4调节剂,CD160调节剂,CD161调节剂,CD27调节剂,CD47调节剂,CD70调节剂,GITR调节剂,HEVEM调节剂,ICOS调节剂,Mer调节剂,NKG2A调节剂,NKG2D调节剂,OX40调节剂,SIRPα调节剂,TIGIT调节剂,Tim-4调节剂,Tyro调节剂,Na+-牛磺酸盐协同转运多肽(NTCP)抑制剂,天然杀伤细胞受体2B4抑制剂,NOD2基因刺激剂,核蛋白抑制剂,核蛋白调节剂,PD-1抑制剂,PD-L1抑制剂,PEG-干扰素λ,肽基脯氨酰异构酶抑制剂,磷脂酰肌醇-3激酶(PI3K)抑制剂,重组清道夫受体A(SRA)蛋白,重组胸腺素α-1,维甲酸诱导基因1刺激物,逆转录酶抑制剂,核糖核酸酶抑制剂,RNA DNA聚合酶抑制剂,短干扰RNA(siRNA),短合成发夹RNA(sshRNA),SLC10A1基因抑制剂,SMAC模拟物,Src酪氨酸激酶抑制剂,干扰素基因刺激物(STING)激动剂,NOD1刺激物,T细胞表面糖蛋白CD28抑制剂,T细胞表面糖蛋白CD8调节剂,胸腺素激动剂,胸腺素α1配体,Tim-3抑制剂,TLR-3激动剂,TLR-7激动剂,TLR-9激动剂,TLR9基因刺激剂,toll样受体(TLR)调节剂,病毒核糖核苷酸还原酶抑制剂,锌指核酸酶或合成核酸酶(TALEN)及其组合。
如本文中所使用,“治疗有效量”或“有效量”是指在剂量下有效并且持续所需时间周期以实现期望的治疗结果的量。乙肝治疗剂的治疗有效量将取决于障碍或症状的性质并取决于特定的试剂,且可以通过本领域技术人员已知的标准临床技术确定。
治疗结果可以是,如,减轻症状、延长存活、改善生活质量等。治疗结果不需要是“治愈”。治疗结果也可以是预防性的。最优选的治疗效果是功能性治愈和乙肝病毒的清除。
在一个优选实施方式中,所述药物经配制通过选自以下的途径施用:口服、直肠、经鼻、经肺、局部、口腔和舌下、阴道、肠胃外、皮下、肌肉内、静脉内、皮内、鞘内和硬膜外。
在一个优选实施方式中,所述药物经配制通过口服施用,优选为片剂或胶囊的形式。
给药途径
本公开的药物或药物组合物通过适合于待治疗病症的任何途径施用。合适的途径包括口服、直肠、鼻、肺、局部(包括口腔和舌下)、阴道和肠胃外(包括皮下、肌肉内、静脉内、皮内、鞘内和硬膜外)等。在某些实施方式中,本文公开的药物或药物组合物通过静脉内注射施用。将会理解,优选途径可根据例如接受者的状况而变化。本公开药物或药物组合物的一个优点在于,它们是口服生物可利用的并且可以口服施用。
药物组合物
在某些实施方式中,在药物组合物中施用通式1的化合物、其衍生物或其药学上可接受的盐。本公开的药物组合物可以用常规载体和赋形剂(其将根据通常的实践选择)配制。片剂将含有赋形剂、助流剂、填充剂、粘合剂等。水性制剂以无菌形式制备,并且当用于通过非口服施用递送时,通常是等渗的。所有制剂将任选地含有赋形剂,例如“Handbook ofPharmaceutical Excipients”(1986)中所述的赋形剂。赋形剂包括抗坏血酸和其它抗氧化剂,螯合剂如EDTA,碳水化合物如葡聚糖,羟基烷基纤维素,羟基烷基甲基纤维素,硬脂酸等。制剂的pH范围为约3至约11,但通常为约7至10。在一些实施方式中,制剂的pH范围为约2至约5,但通常为约3至4。
制剂包括适用于前述施用途径的制剂。制剂可以方便地以单位剂型存在,并且可以通过药学领域熟知的任何方法制备。技术和制剂通常在Remington’s PharmaceuticalSciences(Mack Publishing Co.,Easton,PA)中找到。这样的方法包括使活性成分与由一种或多种辅助成分构成的载体结合的步骤。通常,通过将活性成分与液体载体或细分的固体载体或两者均匀地和紧密地结合在一起,然后根据需要使产品成形,来制备制剂。
适用于口服施用的本发明的制剂可以作为以下形式存在:各自含有预定量活性成分的离散单元,如胶囊剂或片剂;粉末或颗粒;水性或非水性液体中的溶液或悬浮液;或者水包油液体乳剂或油包水液体乳剂。
片剂通过任选地与一种或多种辅助成分一起压制或模制而制成。压制片剂可以通过以下来制备:在合适的机器中压制自由流动形式如粉末或颗粒的活性成分,其任选地与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合。模制片剂可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉末状活性成分的混合物来制备。片剂可任选地包衣或刻痕,并任选地配制,以便自其提供活性成分的缓释或控释。
用于口服使用的制剂也可以呈现为硬明胶胶囊,其中活性成分与惰性固体稀释剂例如磷酸钙或高岭土混合,或呈现为软明胶胶囊,其中活性成分与水或油介质例如花生油、液体石蜡或橄榄油混合。
本公开的药物组合物也可以是无菌可注射制剂的形式,例如无菌可注射水性或油性悬浮液。该悬浮液可以根据已知技术使用上面提到的那些合适的分散剂或润湿剂和悬浮剂配制。无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如在1,3-丁二醇中的溶液,或制备成冻干粉末。可以使用的可接受的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,无菌固定油通常可用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸同样可用于制备注射剂。可以使用的可接受的载体和溶剂包括水、林格氏溶液、等渗氯化钠溶液和高渗氯化钠溶液。
在查阅了下面的实施例之后,本发明的另外的目的、优势和新特征对本领域普通技术人员将变得显而易见。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例
实施例1-应用HepG2-NTCP细胞评价帕立骨化醇(HD009,化合物9)、阿法骨化醇(HD125,化合物18)和骨化二醇(HD135,化合物3)的体外抗HBV活性
化合物配制方法如下:
以配制20mM浓度为例,溶剂DMSO的体积(μl)=样品质量(mg)×纯度÷分子量÷20×106
对照化合物包括ETV(恩替卡韦)(批号:P1214012;99.0%纯度),购自上海泰坦科技股份有限公司;HD131(维生素D2)、HD132(维生素D3)、HD134(度骨化醇),购自上海陶素生化科技有限公司。以上对照化合物的母液浓度为20mM,并在-20℃下保存。
表1.主要试剂和细胞病毒
实验方案
铺细胞和化合物处理
第0天,将HepG2-NTCP铺种到48孔板中(7.5×104个细胞/孔)。
第1天,更换为含2%DMSO的培养基。
第2天,先加入化合物预处理细胞2小时,然后加入D型HBV感染HepG2-NTCP细胞(感染同时加入化合物)。受试化合物稀释3个单药浓度,1个联合用药浓度,2复孔测试。化合物浓度见表2。
第3、5和7天更换一次含化合物的新鲜培养基。
第9天,收集上清,将收集的细胞上清用ELISA法检测HBeAg和HBsAg,qPCR法检测HBV DNA水平。同时,CellTiter-Glo检测细胞活力,收集细胞冷冻保存(备用)。实验流程参见表3。
表2:化合物浓度(单位μM)
表3:实验流程
样品检测
1)qPCR法检测细胞培养上清中HBV DNA的含量
参照QIAamp 96DNA Blood Kit说明书,提取细胞培养上清中的DNA。HBV特异性引物qPCR检测HBV DNA的含量。PCR反应:95℃,10min;95℃,15sec,60℃,1min,40个循环。
2)ELISA法检测细胞培养上清中HBeAg和HBsAg的含量
方法参照试剂盒说明书,方法简述如下:分别取50μl的标准品,样品和对照品加入到检测板中,然后每孔加入50μl酶结合物,37℃孵育60分钟,用洗液洗板后吸干,然后加入50μl预混发光底物,室温避光孵育10分钟,最后酶标仪测定发光值。
3)CellTiter-Glo细胞活力检测
参照CellTiter-Glo试剂盒说明书测定细胞活力,方法简述如下:收集细胞培养上清之后,每孔加入CellTiter-Glo(培养基1:1稀释),室温孵育10分钟,酶标仪测定发光值。
数据分析
HBV DNA抑制率(%)=(1-化合物组样品的HBV拷贝数/DMSO组的HBV拷贝数)×100%
HBe/sAg抑制率(%)=(1-样品的HBe/sAg值/DMSO对照组HBe/sAg值)×100%
结果分析
帕立骨化醇与ETV的检测结果参见表4-6和图1-3。
表4测试化合物的HBV DNA抑制率
表5测试化合物的HBsAg抑制率
表6测试化合物的HBeAg抑制率
以上试验结果显示,帕立骨化醇能有效降低HBV病毒载量。对于20μM帕立骨化醇而言,在降低HBV DNA达64.38%的情况下,还能够同时降低HBsAg和HBeAg分别达到80.48和70.42%。而恩替卡韦正如文献中报道的一样,仅仅能够降低HBV DNA,对于降低HBeAg和HBsAg基本没有效果。可见,帕立骨化醇与恩替卡韦相比,能够同时有效降低HBeAg和HBsAg,从而有望清除乙肝病毒,达到功能性治愈。
阿法骨化醇(HD125)与HD131、HD132、HD134、HD135的检测结果参见表7和图4-8。
表7对照化合物对HepG2-NTCP细胞的EC50
以上试验结果显示,HD125(阿法骨化醇):测试浓度范围内,仅最高浓度10μM有~30%微弱细胞毒性,前两浓度3.33μM、1.11μM对HBsAg及HBeAg有明显抑制,IC50分别为3.091μM、3.681μM,对HBV DNA的抑制较弱,最高抑制率~42%,见图4。HD135(骨化二醇):仅10μM表现出明显细胞毒性,前3~4个浓度点对HBV DNA、HBsAg及HBeAg分别有明显抑制,对各指标抑制的IC50分别为1.895μM,1.62μM,1.698μM,见图8。
HD131(维生素D2):测试浓度范围内无明显细胞毒性,最高浓度10μM对HBV DNA及HBsAg分别有~38%、~34%抑制,对HBeAg的最高抑制率为~37%,浓度在~300nM左右,见图5。
HD132(维生素D3):测试浓度范围内无明显细胞毒性,最高浓度10μM对HBV DNA及HBsAg分别有~11%、~26%抑制,对HBeAg的最高抑制率为~28%,浓度在~300nM左右,见图6。
HD134(度骨化醇):测试浓度范围内无明显细胞毒性,前两浓度3.33μM、1.11μM对HBV DNA、HBsAg及HBeAg分别有明显抑制,对HBeAg的最高抑制率未超50%,见图7。
综上,本发明HD125(化合物18,阿法骨化醇)与HD131和HD132相比,HD125能有效降低HBsAg和HBeAg,EC50分别为3.68μM和3.09μM。而HD134仅仅能够降低HBV DNA和HBsAg,对于降低HBeAg基本没有效果。HD125比HD134具有更好的HBsAg和HBeAg抑制作用,较HD131和HD132的抑制作用更为明显。HD135(骨化二醇)仅10μM表现出明显细胞毒性,对HBV DNA、HBsAg及HBeAg分别有明显抑制。可见,HD125和HD135,能够有效降低HBeAg和HBsAg,从而有望清除乙肝病毒,达到功能性治愈。
实施例2-AAV HBV小鼠模型实验
按照下表7的方式进行给药,参考上文相同的方法检测细胞培养上清中HBV DNA、HBeAg和HBsAg的含量,结果见表8:
表7
给药方式 | 时间 | |
空白对照 | 0,每日一次 | 7天 |
HD125 | 2ug/kg,每日一次 | 7天 |
表8
HD125 | Log HBV DNA | Log HBsAg | Log HBeAg |
0day | 6.56 | 3.41 | 2.66 |
7day | 4.61 | 2.96 | 2.61 |
变化量 | -1.95 | -0.45 | -0.05 |
动物实验结果也表明,HD125(阿法骨化醇)能够有效降低HBV DNA,HBsAg和HBeAg,表现出良好的体内抗病毒效果。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
4.权利要求1-3任一项所述的用途,其特征在于,所述通式1的衍生物为其氘代化合物或其他同位素标记。
5.权利要求1-4中任一项所述的用途,其特征在于,所述病毒性肝炎为乙型肝炎或丁型肝炎。
6.权利要求1-5任一项所述的用途,其特征在于,所述药物用于降低乙型肝炎病毒载量、HBsAg和/或HBeAg水平。
8.权利要求1或2所述式1所示的化合物、其衍生物或其药学上可接受的盐,以及一种或多种另外的治疗剂或预防剂在制备用于降低或清除HBsAg和/或HBeAg的药物中的用途。
9.一种药物组合物,其包含权利要求1或2所示的通式1所示的化合物、其衍生物或其药学上可接受的盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110027380 | 2021-01-10 | ||
CN2021100273808 | 2021-01-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114209706A true CN114209706A (zh) | 2022-03-22 |
Family
ID=80707950
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210016133.2A Pending CN114209706A (zh) | 2021-01-10 | 2022-01-07 | 维生素d类似物用于治疗或预防病毒性肝炎的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114209706A (zh) |
-
2022
- 2022-01-07 CN CN202210016133.2A patent/CN114209706A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112933085B (zh) | 一种化合物在制备治疗或预防病毒性肝炎用药物中的应用 | |
EP3166615B1 (en) | Chelated phosphorotiotated nucleic acid polymers for use in combination with a hbv polymerase inhibitor for the treatment of hepatitis b and hepatitis d virus infections | |
CN114073699A (zh) | 雷帕霉素在治疗或预防乙型肝炎中的应用 | |
CN114832023B (zh) | 老鹳草有效成分用于治疗或预防病毒性肝炎的应用 | |
CN114423423B (zh) | 一种用于治疗或预防病毒性肝炎的药物组合物及其应用 | |
CN115944629A (zh) | 雷帕霉素在治疗或预防乙型肝炎中的应用 | |
CN114949216A (zh) | PI3K和mTOR抑制剂用于治疗或预防病毒性肝炎的应用 | |
CN114209706A (zh) | 维生素d类似物用于治疗或预防病毒性肝炎的应用 | |
CN114224888B (zh) | 兰索拉唑在制备治疗或预防病毒性肝炎用药物中的用途 | |
CN114903891B (zh) | 沙奎那韦在治疗或预防乙型肝炎中的应用 | |
CN114099517B (zh) | 苯并咪唑类化合物在治疗或预防乙型肝炎中的应用 | |
CN114073702B (zh) | 喹诺酮类化合物在治疗或预防乙型肝炎中的应用 | |
CN114053293A (zh) | 杂环基化合物在制备治疗或预防病毒性肝炎药物中的应用 | |
CN114259492A (zh) | 硝唑尼特在治疗乙肝中的应用 | |
CN113440504A (zh) | 二巯丁二钠在制备治疗或预防病毒性肝炎用药物中的用途 | |
CN114681439A (zh) | 芬维a胺在制备治疗或预防病毒性肝炎用药物中的用途 | |
WO2022179575A1 (zh) | 雷帕霉素在治疗或预防乙型肝炎中的应用 | |
CN115337310A (zh) | 一种抗炎剂在制备治疗或预防病毒性肝炎药物的应用 | |
CN115245569A (zh) | 一种用于治疗病毒性肝炎的药物组合物 | |
CN114681614A (zh) | 苯并噁嗪酮类化合物用于治疗或预防病毒性肝炎的应用 | |
CN114533743A (zh) | 一种用于治疗或预防病毒性肝炎的药物组合物 | |
CN114948949A (zh) | Hsp90抑制剂用于治疗或预防病毒性肝炎的应用 | |
CN115518072A (zh) | 一种用于治疗病毒性肝炎的药物组合物 | |
CN116407638A (zh) | 一种用于治疗病毒性肝炎的药物组合物 | |
CN115212191A (zh) | 3,7,11-三甲基-2,6,10-十二烷三烯-1-醇在治疗病毒性肝炎中的应用 |
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 |