CN100506231C - 抗炎组合物及其制药用途 - Google Patents
抗炎组合物及其制药用途 Download PDFInfo
- Publication number
- CN100506231C CN100506231C CNB038134136A CN03813413A CN100506231C CN 100506231 C CN100506231 C CN 100506231C CN B038134136 A CNB038134136 A CN B038134136A CN 03813413 A CN03813413 A CN 03813413A CN 100506231 C CN100506231 C CN 100506231C
- Authority
- CN
- China
- Prior art keywords
- ccr1
- cell
- mip
- compound
- compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims description 28
- 238000000034 method Methods 0.000 title abstract description 24
- 230000003110 anti-inflammatory effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 102000001327 Chemokine CCL5 Human genes 0.000 claims abstract description 18
- 108010055166 Chemokine CCL5 Proteins 0.000 claims abstract description 16
- 102000019034 Chemokines Human genes 0.000 claims abstract description 8
- 108010012236 Chemokines Proteins 0.000 claims abstract description 8
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 claims description 25
- 239000005482 chemotactic factor Substances 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 15
- 102000004500 CCR1 Receptors Human genes 0.000 claims description 13
- 108010017319 CCR1 Receptors Proteins 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Chemical group 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 18
- 201000010099 disease Diseases 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 15
- 230000002757 inflammatory effect Effects 0.000 abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 12
- 208000035475 disorder Diseases 0.000 abstract description 3
- 230000004957 immunoregulator effect Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 53
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 39
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 39
- 238000012360 testing method Methods 0.000 description 30
- 101000577064 Lymnaea stagnalis Molluscan insulin-related peptide 1 Proteins 0.000 description 22
- 101000737895 Mytilus edulis Contraction-inhibiting peptide 1 Proteins 0.000 description 22
- -1 methoxyl group Chemical group 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 18
- 239000011575 calcium Substances 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000012155 cross-linking immunoprecipitation Methods 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 208000015891 sexual disease Diseases 0.000 description 10
- 239000000725 suspension Substances 0.000 description 9
- 210000000265 leukocyte Anatomy 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 6
- 101800004538 Bradykinin Proteins 0.000 description 6
- 102400000967 Bradykinin Human genes 0.000 description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 6
- 102000009410 Chemokine receptor Human genes 0.000 description 6
- 108050000299 Chemokine receptor Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 6
- 229910001424 calcium ion Inorganic materials 0.000 description 6
- 239000000470 constituent Substances 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 206010052779 Transplant rejections Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 230000005540 biological transmission Effects 0.000 description 5
- 230000003399 chemotactic effect Effects 0.000 description 5
- 230000035605 chemotaxis Effects 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 230000002519 immonomodulatory effect Effects 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 210000003889 oxyphil cell of parathyroid gland Anatomy 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 208000012201 sexual and gender identity disease Diseases 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 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
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000002421 anti-septic effect Effects 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000283073 Equus caballus Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000029523 Interstitial Lung disease Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- 208000003455 anaphylaxis Diseases 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 150000003906 phosphoinositides Chemical class 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 210000000582 semen Anatomy 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical class OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 2
- 101100219997 Mus musculus Ccr1 gene Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- KULDXINYXFTXMO-UHFFFAOYSA-N bis(2-chloroethyl) (3-chloro-4-methyl-2-oxochromen-7-yl) phosphate Chemical compound C1=C(OP(=O)(OCCCl)OCCCl)C=CC2=C1OC(=O)C(Cl)=C2C KULDXINYXFTXMO-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical group CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- 230000028023 exocytosis Effects 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940042880 natural phospholipid Drugs 0.000 description 2
- 230000003448 neutrophilic effect Effects 0.000 description 2
- 231100000344 non-irritating Toxicity 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 208000005987 polymyositis Diseases 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 230000008054 signal transmission Effects 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 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 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- FIDRAVVQGKNYQK-UHFFFAOYSA-N 1,2,3,4-tetrahydrotriazine Chemical compound C1NNNC=C1 FIDRAVVQGKNYQK-UHFFFAOYSA-N 0.000 description 1
- BZGWZLIKWOCPLN-UHFFFAOYSA-N 1,3-benzothiazole;quinoline Chemical compound C1=CC=C2SC=NC2=C1.N1=CC=CC2=CC=CC=C21 BZGWZLIKWOCPLN-UHFFFAOYSA-N 0.000 description 1
- AKQIJUCZWUAMNJ-UHFFFAOYSA-N 1,3-benzoxazole;quinoline Chemical compound C1=CC=C2OC=NC2=C1.N1=CC=CC2=CC=CC=C21 AKQIJUCZWUAMNJ-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QSYXZWXIBVKIOH-UHFFFAOYSA-N 1-tert-butylperoxy-2,2-dimethylpropane Chemical compound C(C)(C)(C)OOCC(C)(C)C QSYXZWXIBVKIOH-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- HVTUHSABWJPWNK-UHFFFAOYSA-N 2-[2-chloro-5-[3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)-2-hydroxypropoxy]-4-(methylcarbamoyl)phenoxy]-2-methylpropanoic acid Chemical compound CNC(=O)C1=CC(Cl)=C(OC(C)(C)C(O)=O)C=C1OCC(O)CN1CCC2(OC3=CC=C(Cl)C=C3C2)CC1 HVTUHSABWJPWNK-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 229940124125 5 Lipoxygenase inhibitor Drugs 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
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- AKJDEXBCRLOVTH-UHFFFAOYSA-N Carbetapentane citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C1(C(=O)OCCOCCN(CC)CC)CCCC1 AKJDEXBCRLOVTH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011686 Cutaneous vasculitis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 1
- 241000282323 Felidae Species 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 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
- AMHAQOBUZCQMHN-UHFFFAOYSA-N Indo-1 dye Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C=2NC3=CC(=CC=C3C=2)C(O)=O)N(CC(O)=O)CC(O)=O)=C1 AMHAQOBUZCQMHN-UHFFFAOYSA-N 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 description 1
- 208000034800 Leukoencephalopathies Diseases 0.000 description 1
- 229940122142 Lipoxygenase inhibitor Drugs 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- IUWPPNJCPPZUSD-UHFFFAOYSA-N N1CCOCC1.O1C=NC=C1 Chemical compound N1CCOCC1.O1C=NC=C1 IUWPPNJCPPZUSD-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940123134 Nitric oxide inhibitor Drugs 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
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010035742 Pneumonitis Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 101710193790 Tax1-binding protein 3 Proteins 0.000 description 1
- 102100036221 Tax1-binding protein 3 Human genes 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CAWBRCOBJNWRLK-UHFFFAOYSA-N acetyloxymethyl 2-[4-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]-3-[2-[2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-1h-indole-6-carboxylate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C=2NC3=CC(=CC=C3C=2)C(=O)OCOC(C)=O)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O CAWBRCOBJNWRLK-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 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
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- OFAIGZWCDGNZGT-UHFFFAOYSA-N caramiphen Chemical compound C=1C=CC=CC=1C1(C(=O)OCCN(CC)CC)CCCC1 OFAIGZWCDGNZGT-UHFFFAOYSA-N 0.000 description 1
- 229960004160 caramiphen Drugs 0.000 description 1
- 229940098391 carbetapentane citrate Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 229960003609 cathine Drugs 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 201000005311 drug allergy Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 201000009580 eosinophilic pneumonia Diseases 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- YFHXZQPUBCBNIP-UHFFFAOYSA-N fura-2 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=3OC(=CC=3C=2)C=2OC(=CN=2)C(O)=O)N(CC(O)=O)CC(O)=O)=C1 YFHXZQPUBCBNIP-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000002615 hemofiltration Methods 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-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
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000002788 histamine agent Substances 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PNDZEEPOYCVIIY-UHFFFAOYSA-N indo-1 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C=2N=C3[CH]C(=CC=C3C=2)C(O)=O)N(CC(O)=O)CC(O)=O)=C1 PNDZEEPOYCVIIY-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 102000027411 intracellular receptors Human genes 0.000 description 1
- 108091008582 intracellular receptors Proteins 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 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
- 125000000904 isoindolyl group Chemical class C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 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
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- MKXZASYAUGDDCJ-CGTJXYLNSA-N levomethorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(C)[C@@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-CGTJXYLNSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 210000003887 myelocyte Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960005016 naphazoline Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 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
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical group CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000019353 potassium silicate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 201000009732 pulmonary eosinophilia Diseases 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- XYVVNRCEUUMOAX-UHFFFAOYSA-N quinoline;quinoxaline Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=NC2=CC=CC=C21 XYVVNRCEUUMOAX-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 230000001624 sedative effect Effects 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960003676 tenidap Drugs 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
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- XAGUNWDMROKIFJ-UHFFFAOYSA-J tetrapotassium;2-[2-[[8-[bis(carboxylatomethyl)amino]-6-methoxyquinolin-2-yl]methoxy]-n-(carboxylatomethyl)-4-methylanilino]acetate Chemical compound [K+].[K+].[K+].[K+].C1=CC2=CC(OC)=CC(N(CC([O-])=O)CC([O-])=O)=C2N=C1COC1=CC(C)=CC=C1N(CC([O-])=O)CC([O-])=O XAGUNWDMROKIFJ-UHFFFAOYSA-J 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
本发明涉及包含活性化合物的药物组合物，其抑制趋化因子、MIP-1α和RANTES活性。本发明还涉及使用本药物组合物治疗炎性和免疫调节性紊乱和疾病的方法。
Description
联邦赞助研究或开发
防御高级研究项目代理(DARPA)基金No.N65236-99-1-5420。
发明背景
本发明涉及包含活性化合物及其药物可接受的盐的药物组合物，其对于不同的趋化因子，例如MIP-1α和RANTES与CCR1受体的结合具有抑制作用。本发明还涉及应用上述药物组合物治疗炎性和免疫调节性紊乱与疾病的方法。
人体健康有赖于身体发现、消灭外来的有可能侵占个体有用资源和/或诱发疾病的病原体的能力。免疫系统，其包括白细胞(白细胞(WBCs)：T和B淋巴细胞，单核细胞，嗜酸性细胞，嗜碱性细胞，和中性粒细胞)、淋巴组织和淋巴管，是人体的防御系统。为了抵御感染，B和T淋巴细胞在身体内循环，与抗原呈递细胞相互作用，检测病原体。一旦检测到侵入物，T淋巴细胞聚集在感染部位，消灭病原体。趋化因子作为T淋巴细胞，中性粒细胞和巨噬细胞聚集和激活的分子指向标，标志病原体方位。
当保护人体免受病原体侵袭时，免疫系统也会产生故障。趋化因子发出不适当的信号将导致产生炎性紊乱，例如类风湿性关节炎，多发性硬化症及其他疾病。类风湿性关节炎中，骨关节中未调节的趋化因子吸引并活化浸润的巨噬细胞和T-细胞。这些细胞的活动诱发滑膜细胞增殖，导致炎症以及最终的骨和软骨损耗(DeVries，Ran et al.1999)。某些脱髓鞘性病例如多发性硬化症的一个标志就是趋化因子-介导的巨噬细胞和T细胞聚集至中枢神经系统(Kennedy和Karpus 1999)。聚集至移植物的破坏性WBCs的趋化因子涉及其随后的排异反应(DeVries，Ran et al.1999)。由于趋化因子在炎症和淋巴细胞发展过程中扮演了极其重要的角色，特异性操纵其活性的能力对于改善和阻断目前还没有令人满意的治疗方法的疾病将产生巨大的影响。另外，在没有昂贵的免疫抑制剂药物的全身和并发作用的情况下移植排斥可能能减至最小。
趋化因子，一组大于40的小肽(7-10kD)，连接在WBCs表达的受体上，通过G-蛋白-偶联的信号级联发出信号调节它们的化学趋化和化学刺激剂功能。受体可能连接一个以上的配体；例如，受体CCR1连接RANTES(活化时受调节的正常T细胞表达的因子)，MIP-1α(巨噬细胞炎性蛋白)和MIP-1β趋化因子。迄今为止，已知24种趋化因子受体。趋化因子的绝对数目，多配体结合受体，和WBCs的不同受体特性保证可严格控制的和特异性的免疫应答(Rossi和Zlotnik 2000)。趋化因子活性可通过调节其相应的受体而加以控制，治疗相关的炎性和免疫性疾病，有利于器官和组织移植。
受体CCR1及其趋化因子配体，包括，例如MIP-1α，MIP-1β，和RANTES，是有希望的治疗靶点，因为它们涉及类风湿性关节炎，移植排斥(均综述于(DeVries，Ran et al.1999))，和多发性硬化症(Fischer，Santambrogio et al.2000；Izikson，Klein et al.2000；Rottman，Slavin et al.2000)。事实上，已发现功能-阻断性抗体，修饰的趋化因子受体配体和小分子有机化合物，并成功地证明了其中一些具有预防或治疗某些趋化因子—介导的疾病的作用(综述于(Rossi和Zlotnik2000))。特别是，在类风湿性关节炎的一个实验模型中，当给予一种信号-阻断性、修饰的-RANTES配体时，疾病的发展得到减弱(Plater-Zyberk，Hoogewerf et al.1997)。尽管使用功能-阻断性抗体和小分子肽治疗是有前景的，其缺点是有降解的危险，给药时半衰期极短，并且大多数蛋白开发和制造费用昂贵。小分子有机化合物比较合适，因为它们在体内半衰期较长，产生作用所需剂量较小，能够经常口服给药，因此较为便宜。某些CCR1有机拮抗物在前已经进行了描述(Hesselgesser，Ng et al.1998；Ng，May et al.1999；Liang，Mallariet al.2000；Liang，Rosser et al.2000)。由于这些化合物已显示出在某些动物模型中治疗疾病是有效的(Liang，Mallari et al.2000)，本领域中需要更多可用于药物中的化合物。申请人已发现CCR1的有效有机拮抗物，有望成为本领域重要的工具。
本文公开类型的哌嗪衍生物是已知的抗炎剂(参见例如，WO 98/56771，W097/44329，WO 99/37651，WO 99/37619，WO 00/53600)。本文公开的特定的哌嗪衍生物以前从未认定被为CCR1拮抗物。
发明概述
在一个具体实施方式中，本发明提供了包含药物可接受的载体和可抑制各种趋化因子与CCR1受体结合的活性化合物的组合物，该趋化因子包括例如MIP-1α和RANTES。
在另一个具体实施方式中，本发明提供一种阻断CCR1受体的方法，包括给予一种抑制多种趋化因子活性的化合物，该趋化因子包括例如MIP-1α和RANTES。
在另一个具体实施方式中，本发明提供治疗炎性和免疫调节性紊乱和疾病的方法，包括给予本发明所述组合物。
发明详述
本发明提供了包括药物可接受的载体和抑制多种趋化因子与CCR1受体结合的活性化合物的组合物，该趋化因子包括例如主要配体MIP-1α，MIP-1β，MIP-1γ，骨髓祖细胞抑制因子-I(XIF-I)，血液滤过物(hemofiltrate)C-C-I(HCC-1)，白细胞诱素和RANTES。
本发明组合物可用于治疗炎性紊乱。
定义
“烷基”是指一种饱和脂肪族基团，包括直链烷基，支链烷基，或环烷基。在优选的实施方式中，直链或支链烷基主链上碳原子数目为10或更少，更优选的是6或更少，最优选的是4或更少。同样，优选的环烷基在其环结构上有3—10个碳原子，更优选在环结构上有3—6个碳原子。烷基的实例包括，但不限于，甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、叔丁基、仲丁基、环丁基、戊基、己基、环己基等等。优选甲基和乙基。
“烷氧基”是指通过氧原子连接在母体分子部分上的如前述定义的烷基。烷氧基的实例包括，但不限于，甲氧基、乙氧基、丙氧基、异丙氧基、正-丁氧基、叔丁氧基、新戊氧基和正-己氧基。
“芳基”是指任何含有5—10个碳原子的单价芳香碳环基团。芳基可以是二环(即苯基(或Ph))或多环(即萘基)，也可以是非取代或取代的。优选的芳基包括苯基、萘基、呋喃基、噻吩基、吡啶基、吲哚基、喹啉基或异喹啉基。
“卤代烷基”是指被一个或多个卤素原子取代的如上述定义的烷基。卤代烷基的实例包括，但不限于，三氟甲基、二氟甲基、三氯甲基、氯乙基、溴丁基、2-三氟乙基、1-氟甲基-2-氟乙基、3-溴-2-氟丙基、1-溴甲基-2-溴乙基等等。特别优选三氟甲基。
“卤素”是指氟、氯、溴和碘。
“杂环基”是指稳定的、饱和的、部分不饱和或芳族基团，包含5—10个环原子，优选5或6个环原子。环可被取代基取代一次或多次。环可以是单、双或多环。杂环基由碳原子和1—3个杂原子组成，杂原子可独立地选自氮、氧和硫。杂环基的实例包括吖啶、苯并噻唑啉、苯并咪唑、苯并呋喃、苯并吡喃、苯并噁唑啉、苯并噻吩、苯并噻唑、苯并噻吩基、咔唑、噌啉、呋喃、咪唑、1H-吲唑、吲哚、异吲哚、异喹啉、异噻唑、吗啉、噁唑(即1，2，3，-噁二唑)、吩嗪、吩噻嗪、吩噁嗪、酞嗪、哌啶、哌嗪、喋啶、嘌呤、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑啉、喹啉、喹噁啉、四氢呋喃、四氢喹啉基、1，2，3，4-四氢异喹啉基、四氢噻吩基及其亚砜和砜衍生物、硫吗啉、噻唑、1，3，4-噻二唑、噻吩(thiene)、噻吩、1，3，5-三嗪、三唑(即1，2，3，-三唑)等等。
“取代的”是指包含至少一个，优选1-3个取代基的部分。合适的取代基包括氢(H)和羟基(-OH)、氨基(-NH2)、氧(-O-)、羰基(-CO-)、巯基、烷基、烯基、炔基、烷氧基、卤素、腈、硝基、芳基和杂环基。这些取代基任选地被1—3个取代基进一步取代。取代的取代基的例子包括，酰胺、烷基巯硫、烷基磺基、烷氨基、二烷氨基、羧化物、烷氧羰基、烷芳基、芳烷基、烷杂环基等等。
抑制趋化因子、MIP-1α和RANTES活性的化合物
在一个具体实施方式中，本发明活性化合物是式(1)化合物：
其中n是0、1、或2；
Y是氧或硫；
R1、R2、和R3各自独立地为氢、烷基、烷氧基、卤素、卤代烷基或硝基。
优选的，活性化合物是式(2)：
其中n是0、1、或2；
Y是氧或硫；并且
R1、R2、和R3各自独立地为氢、烷基、烷氧基、卤素、卤代烷基或硝基。
特别优选的，化合物(1)中R1和R2是氢，R3是卤素(特别优选的是氯或氟)或氢。
本发明应用的化合物可通过商业途径购得，也可根据已知方法制备(参见例如FR 1,441，071和JP 63-41907)。
测试
要证明本发明化合物是CCR1受体拮抗剂，如果它们可以抑制趋化因子MIP-1α和RANTES的活性即可确定。优选的所述化合物具有以下特性：
(1)可有效地抑制趋化因子MIP-1α或RANTES与CCR1受体结合；
(2)显著抑制对于CCR1的Ca2+应答；和
(3)有限的非特异性Ca2+应答。
体外标准结合测试可用于证实化合物与CCR1受体的亲和力(从而通过与受体的竞争性结合抑制MIP-1α和RANTES的活性)。见下述文实施例。优选地，活性化合物IC50值<10μM，更优选地，<5μM，最优选地<1μM。
抑制MIP-1α和RANTES的活性的化合物影响MIP-1α和RANTES刺激的细胞内Ca2+浓度。配体与CCR1受体的结合导致G-蛋白诱导的磷脂酶C活化，其导致磷脂酰肌醇磷酸转化为磷酸肌醇和二酰基甘油。磷酸肌醇接着与细胞内受体结合，将Ca2+释放至细胞质中。除Ca2+从细胞内贮库释放使Ca2+浓度升高外，磷酸肌醇与其受体的结合导致细胞外钙离子穿过膜进入细胞内的流量增大。因此，由MIP-1α和RANTES引起的CCR1受体的激活，以及随后由本发明化合物产生的活化抑制，均可通过测定细胞内游离的Ca2+水平的增加确定。代表性地，也可以通过使用钙-敏感的荧光探针例如quin-2、fura-2和indo-1完成。参见下文实施例。活性化合物阻断Ca2+应答的作用依赖于存在的活性化合物和趋化因子的数量。一般而言，当趋化因子为10nM时，10μM活性化合物能够产生20-100％的Ca2+应答抑制作用。
测定活性化合物是否产生了非特异性Ca2+应答，可以通过下述方法进行：加入活性化合物，按照上述方法测量所述的Ca2+应答，随后加入一种已知的其他趋化因子受体拮抗剂(例如缓激肽或SDF-1，一种CXCR4配体)。比较应答结果表明活性化合物是非特异性结合。
药物组合物
用于给予活性化合物的药物组合物可以常规地以剂型单位的形式存在，可以以药物领域公知的任一种方法制备。所有的方法均包括下述步骤，将活性化合物与构成一种或多种辅助成分的载体混合。一般而言，药物组合物如下述制备：将活性化合物与液态载体或精细分割的固态载体或二者混合，然后，如果需要，将产物加工成希望的制剂。在药物组合物中，活性化合物的含量足以对疾病的过程或状况产生预期的作用。
包含活性化合物的药物组合物可以是适合口服的剂型，例如，片剂、含片、锭剂、含水或油性混悬液、分散性粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂。用于口服的组合物可通过任何生产药物组合物领域已知的方法制备，这些组合物还可包括一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂，以提供药学上美观和可口的制剂。片剂包括活性成分并混合以无毒的药物可接受的适于制备片剂的赋形剂。赋形剂例如为惰性稀释剂，例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；成粒剂或崩解剂，例如玉米淀粉、或海藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；及润滑剂，例如硬脂酸镁、硬脂酸或滑石。片剂可以不包衣或通过已知的技术包衣，以达到延迟崩解、在胃肠道吸收从而在更长时间内提供持续作用。例如，缓释材料可使用单硬脂酸甘油酯或二硬脂酸甘油酯。它们还可以通过美国专利4,256,108、4,166,452、和4,265,874公开的技术包衣以形成可控制释放的渗透性治疗片剂。
口服制剂也可为硬明胶胶囊，其中活性组份与惰性固态稀释剂混合，例如，碳酸钙、磷酸钙或高岭土；或软明胶胶囊，其中活性组份与水或油介质混合，例如花生油、液态石蜡或橄榄油。
水性混悬液包括活性物质，它们与适合制备水性混悬液的赋形剂混合。这些赋形剂是悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟基-丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶；分散剂或湿润剂可以是天然磷脂，例如卵磷脂、或烯化氧与脂肪酸的缩合物，例如聚氧乙烯硬脂酸酯、或环氧乙烷与长链脂肪醇的缩合物，例如十七烯氧鲸蜡醇、或环氧乙烷与脂肪酸和己糖醇的部分酯的缩合物，例如聚氧乙烯山梨糖醇单油酸酯、或环氧乙烷与脂肪酸和己糖醇酐的部分酯的缩合物，例如聚乙烯去水山梨糖醇单油酸酯。水性混悬液还可包括一种或多种防腐剂，例如乙基、或正-丙基对-羟苯甲酸酯，一种或多种着色剂，一种或多种矫味剂，和一种或多种甜味剂，例如蔗糖或糖精。
油性混悬液可通过将活性组份悬浮于植物油中配制，例如花生油、橄榄油、芝麻油或椰子油，或悬浮于矿物油中例如液态石蜡。油性混悬液可以包括一种增稠剂，例如蜂蜡、固体石蜡或鲸蜡醇。甜味剂如上述列举，可加入矫味剂以制得口感良好的制剂。这些组合物可加入抗氧化剂例如抗坏血酸进行保存防腐。
通过加入水而适于制备水性混悬液的分散性粉末和颗粒提供了与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性组份。合适的分散剂或湿润剂和助悬剂的例子如上文所述。其他赋形剂，例如甜味剂、矫味剂和着色剂，也可使用。
本发明药物组合物还可为水包油乳液的形式。油相可以是植物油，例如橄榄油或花生油，或矿物油，例如液态石蜡或其混合物。合适的乳化剂可以是天然树胶例如阿拉伯胶或西黄蓍胶，天然磷脂例如大豆磷脂、卵磷脂、和脂肪酸和己糖醇酐的酯或部分酯，例如去水山梨糖醇单油酸酯，和所述部分酯与环氧乙烷的缩合物，例如聚氧乙烯脱水山梨糖醇单油酸酯。乳剂还包括甜味剂和矫味剂。
糖浆和酏剂可与甜味剂配制，例如甘油、丙二醇、山梨糖醇或蔗糖。这种制剂还可包括湿润剂、防腐剂、矫味剂和着色剂。
药物组合物可为无菌可注射水性或油性混悬液形式。混悬液可使用上文所述的合适的分散剂或湿润剂和助悬剂，根据已知技术配制。无菌可注射制剂也可以是在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液，例如在1，3-丁二醇中的溶液。可接受的载体和溶剂中能够应用的是水、林格溶液、和等渗氯化钠溶液。另外，无菌非挥发油通常作为溶剂或混悬介质而使用。基于此目的，任何非刺激性非挥发性油均可使用，包括合成的甘油单酯或甘油二酯。另外，发现脂肪酸例如油酸可用于制备可注射制剂。
本发明化合物还可以栓剂形式给药，用于直肠给药。这些组合物可通过混合药物与合适的非刺激性赋形剂制备，赋形剂常温下是固态但在直肠温度下是液态，从而在直肠中熔化释放出药物。这些材料是可可油和聚乙二醇。
对于局部应用，可以使用包含本发明化合物的霜、软膏、胶冻、溶液或混悬液等。(针对本申请的目的，局部应用包括口洗剂和漱口剂。)
本发明药物组合物和方法可以进一步包括本文中记载的其他治疗活性化合物，它们通常用于治疗上文所述的病理状况。
在治疗或预防需要调节趋化因子受体的状况中，适当的剂量水平一般是大约0.01-500mg/kg患者体重/天，可以以单剂或多剂给药。优选的，剂量水平为约0.1至约250mg/kg/天；更优选，约0.5至约100mg/kg/天。适当的剂量水平可为约0.01至250mg/kg/天，约0.05至100mg/kg/天，或约0.1至50mg/kg/天。在此范围内剂量可以是0.05-0.5，0.5-5或5-50mg/kg/天。对于口服给药，优选组合物为片剂形式，包含1.0-1000mg活性组份，特别是根据治疗的病人的症状调节剂量为1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0、和1000.0mg活性组份。化合物每天给药1-4次，优选每天一次或两次。
可以理解的是，对于任何特定患者，特定剂量水平和给药频率都是不同的，其依赖于包括使用的特殊化合物的活性、代谢稳定性、化合物作用时间、年龄、体重、一般健康、性别、饮食、给药方式和时间、排泄率、联合用药、特定状况的严重性，和接受治疗的宿主等各种因素。
阻断CCR1受体的方法
本发明还提供了一种抑制MIP-1α或RANTES与CCR1受体结合的方法，通过在适合抑制趋化因子和CCR1受体结合的条件下使上文所述组合物与表达CCR1受体的细胞接触而实现。
治疗炎性和免疫调节紊乱和疾病的方法
本发明还提供了一种治疗炎性疾病的方法，包括给予需要的患者治疗有效量的上文所述的组合物足够治疗炎性疾病的时间。“治疗”是指预防、抑制或缓解紊乱或症状。
CCR1提供了一个在哺乳动物，例如人体内干扰或促进嗜酸性细胞和/或淋巴细胞功能的靶点。抑制CCR1的化合物对于出于治疗目的的调节嗜酸性细胞和/或淋巴细胞功能尤其有效。相应地，本发明涉及对于预防和/或治疗各种炎性和免疫调节性紊乱和疾病有效的化合物。
例如，一种可抑制一项或多项CCR1功能的化合物可用于抑制(即减少或预防)炎症。结果是，可抑制一种或多种炎症过程，例如白细胞迁移、趋化性、胞吐(例如酶、组胺的)或炎性介质释放。例如，可根据本发明方法抑制对于炎性位点的嗜酸细胞性浸润(如哮喘)。
同样地，一种可促进一项或多项CCR1功能的化合物可用于刺激(诱导或增强)炎症应答，例如白细胞迁移、趋化性、胞吐(如酶、组胺的)或炎性介质释放，造成炎症过程的有益刺激。例如，会聚集嗜酸性细胞以用于抵抗寄生虫感染。
除灵长类，例如人之外，各种其他的哺乳动物可根据本发明的方法进行治疗。例如，哺乳动物，包括，但不限于，牛、绵羊、山羊、马、狗、猫、豚鼠、老鼠或其它牛类、羊类、马类、犬类、猫科、啮齿动物、鼠类物种均可被治疗。而且，该方法还可用于治疗其他物种，例如鸟类物种(如鸡)。
与炎症或感染相关的疾病或状况均可使用本发明的方法进行治疗。在一个优选的具体实施方式中，疾病或状况是指其中的嗜酸性细胞和/或淋巴细胞的功能被抑制或增强，以达到调节炎性应答的目的、
可用CCR1抑制剂治疗的人或其他物种的疾病或状况包括，但不限于：炎性或变应性疾病和状况，包括呼吸系统变应性疾病例如哮喘、过敏性鼻炎、过敏性肺部疾病、过敏性肺炎、嗜酸细胞性肺炎(如吕弗勒(氏)综合征，慢性嗜酸性细胞性肺炎)，迟发型过敏性间质性肺病(ILD)(如特发性肺纤维化或伴随类风湿性关节炎的ILD、系统性红斑狼疮、强直性脊柱炎、系统性硬化症、斯耶格伦(氏)综合征、多发性肌炎或皮肌炎)；全身性过敏反应或超敏反应，药物变态反应(如对于盘尼西林、头孢菌素类)，昆虫螫伤变态反应；自身免疫性疾病，例如类风湿性关节炎、银屑病关节炎、多发性硬化症、脑白质病、脑脊髓炎、阿耳茨海默(氏)病、系统性红斑狼疮、重症肌无力、青少年型糖尿病；肾小球性肾炎、自身免疫性甲状腺炎、贝切特(氏)病；Guillian-Barre综合征、急性细胞介导的移植排斥(例如肾移植排斥)、移植排斥(如在移植术中)，包括同种异体移植物排斥或移植物抗宿主病；uricaria、皮肤血管炎、炎性肠病，例如克隆(氏)病和溃疡性结肠炎；脊柱关节病；硬皮病；银屑病(包括T-细胞介导的银屑病)和炎性皮肤病例如皮炎、湿疹、特应性皮炎、过敏性接触皮炎、荨麻疹；血管炎(如引起坏死的，表皮的，和过敏性脉管炎)；嗜酸细胞性肌炎，嗜酸细胞性筋膜炎；白细胞浸润皮肤或器官的癌症。其中不良炎症应答能够被抑制的其他疾病或状况也可进行治疗，包括但不限于，再灌注损伤、再狭窄、动脉粥样硬化、某些血液恶性肿瘤、细胞因子诱导的中毒(如脓毒性休克、内毒素性休克)、多肌炎、皮肌炎。因此本发明化合物可用于预防或治疗多种炎性和免疫调节性紊乱和疾病。
体外标准测试可用于证实本发明组合物治疗炎性紊乱的有效性，包括多发性硬化症实验性自身免疫性脑脊髓炎的动物模型和类风湿性关节炎的佐剂诱导的关节炎模型。
本发明组合物可通过口服、胃肠外(如肌内、腹膜内、静脉内、ICV、脑池内注射或输注，皮下注射或植入)、吸入喷雾、鼻、阴道、直肠、舌下、或局部给药途径给药，可单独或共同配制成合适的剂量单位制剂，其中含有适于每种给药途径的无毒的药物可接受的载体，佐剂和赋形剂。除了治疗温血动物，例如大鼠、小鼠、马、牛、羊、狗、猫、猴子等，本发明组合物对于治疗人也有效。
联合治疗
如上所述调节趋化因子受体活性从而预防和治疗炎性和免疫调节性紊乱和疾病的联合治疗，通过本发明化合物和其他已知具有同样作用的化合物联合进行举例说明。
例如，在治疗或预防炎症时，本发明化合物可与抗炎或止痛剂结合，例如阿片激动剂；脂加氧酶抑制剂，例如5-脂加氧酶抑制剂；环加氧酶抑制剂，例如环加氧酶-2抑制剂；白介素抑制剂，例如白介素-1抑制剂；NMDA拮抗剂；氧化氮抑制剂或氧化氮合成抑制剂；非甾体抗炎剂；或细胞因子抑制性抗炎剂，例如扑热息痛，阿司匹林，可待因，芬太尼，布洛芬，吲哚美辛，痛力克，吗啡，萘普生，非那西汀，吡罗昔康；甾体镇痛药，舒芬太尼，sunlindac，替尼达普等。同样地，本发明的化合物可与下述药物联合给药：疼痛缓解剂；增效剂例如咖啡因，H2-拮抗剂，二甲硅油，氢氧化铝或氢氧化镁；解充血药例如苯福林，n-去甲麻黄碱，伪麻黄碱，氧甲唑啉，肾上腺素，萘唑啉，丁苄唑啉，环己丙甲胺，或左旋-脱氧-麻黄素；止咳药例如可待因，二氢可待因酮，卡拉美芬，咳必清，或右旋甲吗喃；利尿剂；和镇静或非镇静抗性组胺剂。
下述实施例用于举例说明本发明，并不限于此。
实施例
实施例1：材料和方法
A.化合物样本
此处使用的化合物样本包括商业途径购得的小分子。源培养板包括在二甲基亚砜(DMSO)中的1或5mg/ml各个化合物。根据这些CLIP(化合物库)，制作培养板，其中每孔加入10种化合物，用20％DMSO稀释至5-50μg/ml的浓度。向检验板上滴加一等分20μl的每种混合物，在-20℃条件下储存直至使用。
B.细胞
CCR1转染子
CCR1-NSO细胞
表达稳定的转染子细胞系的CCR1(CCR1-NSO)在Iscove′s改良的Dulbecco′s培养基(IMDM)中培养，培养基含有4.5g/L葡萄糖，5％胎牛血清(FBS)，10mN HCl，250μg/l黄嘌呤(来自于0.1NNaOH中100X黄嘌呤贮存液)，15μg/l次黄嘌呤(来自于0.1N NaOH中100X次黄嘌呤贮存液)，10mg/L胸苷(来自于H2O中100X胸苷贮存液)，50μM β-巯基乙醇(BME)(来自于H2O中1000X BME贮存液)，和1.5mg/L霉酚酸(来自于乙醇中2.5mg/ml霉酚酸贮存液)。细胞在5％CO2/95％空气，100％湿度，37℃条件下生长，当浓度为0.5-1.0×106细胞/ml时进行收集。细胞以1:4每周传代培养两次。
CCR1-293细胞
用人CCR1稳定转染人胚肾腺病毒-转化的细胞系293(美国典型培养物保藏中心(ATCC)；Manassas，VA)。pIRESpuro载体(Clontech；Palo Alto，CA)被工程化以包含一个促乳素信号序列，FLAG-表位克隆至EcoRV-Not I限制位点。人CCR1cDNA克隆被亚克隆至Not I位点，这样插入片段就可操作性连接到强pCMV启动子上。细胞在Dubecco′s改良的Eagle′s培养基中的2μg/ml嘌呤霉素选择下，在5％CO2/95％空气，100％湿度，37℃条件下成长，该培养基中补充了2mM L-谷氨酰胺，1.5g/L碳酸氢钠，0.1mM非必需氨基酸，1.0mM丙酮酸钠，10％胎牛血清。细胞以1：5每周传代培养两次，在1×106细胞/ml时进行收集。
THP-1细胞
THP-1细胞得自ATCC，在RPMI-1640培养基中作为悬浮液培养，该培养基补充了2mM L-谷氨酰胺，1.5g/L碳酸氢钠，4.5g/L葡萄糖，10mMHEPES，1mM丙酮酸钠，0.05％ 2-巯基乙醇和10％ FBS进行补充。细胞在5％CO2/95％空气，100％湿度，37℃条件下成长，以1：5每周传代培养两次，在1×106细胞/ml时进行收集。
C.测定
CCR1配体结合抑制
离心表达CCR1的细胞，在分析缓冲液中(20mMHEPES pH7.1，140mMNaCl，1mM CaCl2，5mM MgCl2，和0.2％牛血清白蛋白)再悬浮，达到浓度为5.6×106细胞/ml(CCR1-NSO)或2.2×106细胞/ml(CCR10293)。如下述方法进行筛选实验。首先，将0.09ml细胞(5×105 CCR1-NSO细胞/孔或2×105CCR1-293细胞/孔)加入含有化合物的测试培养板中，得到的每种化合物的最终浓度为约2-10μM。然后加入0.09ml用测试缓冲液稀释至最终浓度为约50pM，收率约30,000cpm每孔的125I标记的MIP-1α(购自Amersham；Piscataway，NJ)，密封培养板，4℃条件下在振荡平台中温育约3小时。抽吸反应物至在真空细胞收集器(Packard Instruments；Meiden，CT)上预先浸渍在0.3％聚乙烯亚胺(PEI)溶液中的GF/B玻璃滤器。在每孔中加入闪烁液(50μl，Microscint 20，Packard Instruments)，密封培养板，在一个高计数闪烁计数器(Packard Instruments)中进行放射性测量。只包含稀释剂(用于总计数)或过量的MIP-1α或MIP-1β(1μg/ml，用于非特异性结合)的对照孔用于计算每组化合物的占抑制总量的百分比。完成CLIP培养板测试后，证实了抑制率为40％或更高的孔。一经证实，CLIP的各个化合物就要接受反应性(解褶积步骤)测试。IC50值是能够减少标记的MIP-1α与受体结合的50％的所需浓度。
钙动员
为了探测细胞内储存的钙的释放，培养的细胞在细胞培养基中与3μMINDO-1AM染料(分子探针；Eugene，OR)在室温下温育45分钟，用磷酸盐缓冲盐水(PBS)洗涤。加入INDO-1AM后，细胞在流通缓冲液(Hank′s平衡盐溶液(HBSS)和1％FBS)中再悬浮。使用国际光子技术分光光度计(国际光子技术；NewJersey)测量钙动员，在350nm激发，在400nm和490nm处双重同步记录荧光发射。相对细胞内钙水平表示为400nm/490nm发射比。37℃条件下进行试验，在样品杯中连续混合，每个样品杯含有106细胞/2ml流通缓冲液。使用的趋化因子配体范围为1-100nM。根据时间标绘发射比(代表性地，2-3分钟)。在10秒时加入候选的配体阻断性化合物(10-20μM)，然后在60秒时加入趋化因子(MIP-1α；R & D系统；Minneapolis，MN)，在150秒时加入对照趋化因子(缓激肽；ICN制药公司，Costa Mesa，CA)。在某些实验中，同时加入候选的阻断化合物和细胞，40秒后再加入MIP-1α。
趋化性测试
使用5μm孔聚碳酸酯、聚乙烯吡咯酮包被的过滤器在96-孔趋化室(Neuroprobe；Gaithersburg，MD)进行趋化性测试。以基质-衍生的因子(SDF-1)作为特异性对照品。下部的室含有29μl，0.1nM MIP-Iα和多种量的抑制剂，上部的室在20μl中含100,000THP-1细胞。趋化室在37℃温育1-2小时，利用CyQuant测试(Molecular Probes)、测量核酸含量的荧光染料方法和显微镜观察确定下部的室中的细胞数量。
实施例2：CCR1结合MIP-Iα的抑制剂的检验
A.测试
为了检验阻止受体CCR1与配体结合的小有机分子，进行测试以探测在细胞表面与表达外源性CCR1的细胞结合的放射性配体(MIp-Iα)。如果一种化合物能够抑制结合，不管其是否是竟争性抑制，当与未抑制的对照进行比较时，将观察到较少的放射性计数。
构建在细胞表面组成型表达人CCR1的NSO鼠类骨髓瘤细胞系(CCR1-NSO)和人胚胎肾(HEK)癌细胞系(CCR1-293)这些细胞缺少结合MIP-Iα的其他趋化因子受体。在CLIP培养板中向每个孔加入相同数量的细胞，其中每孔含有10种候选的有机化合物。用放射标记的MIP-Iα温育细胞。洗涤细胞以移除未结合的配体，通过定量放射性计数确定结合的配体。通过未用任何有机化合物温育的细胞确定总计数；用未标记配体和标记的配体温育细胞，确定非特异性结合。抑制百分比以下述公式计算：
％抑制＝1-[(样品cpm)-(非特异性cpm)]/[(总cpm)-(非特异性cpm)]×100
B.使用CCR1-NSO细胞从化合物库中鉴定的抑制剂
在测试化合物的第1组中，标准化的标准差是19％；因此，确认的显著抑制是大于38％；40％抑制是选择的阈值。在受试孔数目中，58个孔的内容物抑制40％或更多的MIP-Iα结合。这58个孔的内容物在CLIP中重新测试，其中6个抑制40％或更多的结合。这一结果表明6个孔中的每一个中的10种化合物至少有一种能够抑制MIP-Iα与CCR1结合。为了确认每个孔中究竟是10种化合物中的哪一种抑制了MIP-Iα的CCR1连接，测试每一种单独的化合物在测试中的抑制活性以对合并物解褶积。由于某些化合物可能共同作用以抑制结合，而解褶积测试只适用于单独检测化合物，因此本试验中没有找出联合作用有效而单独作用无效的化合物。鉴定三种候选化合物：
和
在第二组化合物的筛选中，标准化的标准差是17％，表明34％或更多的抑制活性是显著的：此外，阈值为40％。这些CLIPs产生显示出高于40％抑制的39个孔。当再次作为CLIPs被筛选时，14个孔减少了超过40％的配体。单独测试化合物以鉴定13个抑制性候选物；
C.使用CCR1-293细胞从化合物库中鉴定的抑制剂
使用CCR1-293细胞，其以更高水平表达CCR1，结果是提高了噪音与信号比标准化的标准差，大约为10％。筛选第1组化合物，46个孔在初始筛选中显示出大于20％的配体结合抑制，CLIP中的10个孔在第二次筛选中抑制配体结合。单独测试化合物，鉴定出6个候选物：
至于使用CCR1-293细胞进行的关于第1组化合物的测试，第2组化合物筛选的标准化的标准差更小.很有可能是由于使用了这些细胞。在第1个试验中抑制结合的35个CLIP孔中有8个孔得到验证化合物的个别检验鉴定出3个候选物；
和
实施例3：剂量反应曲线
为了确定一种候选化合物对于CCR1的亲和性，以及确定其抑制配体结合的能力，在1×10-8-1×10-4M范围的化合物浓度滴定抑制活性。这项测试基本上等同于CLIP筛选，除了化合物用量发生了变化；细胞数量和配体浓度保持不变。只有本实验时可商业购得的化合物进行了滴定。在鉴定的22个候选物中，下述16个进行了剂量反应试验：
CCX-3343、CCX-1057、CCX-1307、CCX-1513、CCX-238、CCX-3345、CCX-3493、CCX-4425、CCX-4462、CCX-4682、CCX-469、CCX-5062、CCX-5119、CCX-541、CCX-6019和CCX-6530。
不能以剂量依赖性方式抑制MIP-Iα结合的测试化合物是CCX-238、CCX-4425、和CCX-4462。抑制活性根据其对于CCR1亲合力的不同而变化的化合物如表1所示。
表1.CCR1-MIP-Iα结合的亲和值，从最高往最低排列
化合物CCX-541和CCX-469显示出的CCR1亲和值低于1μM。化合物CCX-5062、CCX-3345、和CCX-3343具有阻断活性，但在最高测试浓度时不能够完全抑制MIP-Iα结合；估计它们的亲和值大约为2μM。虽然化合物CCX-6019、CCX-4682、CCX-1307和CCX-1057显示由阻断活性，它们的CCR1亲和值较低，为18-45μM。虽然鉴定出很多化合物能够抑制CCR1与MIP-Iα配体结合，只有两个化合物具有高CCR1亲和值：CCX-541和CCX-469。鉴定出了其他的亲和值较低的MIP-Iα结合抑制性化合物，但是由于抑制性质竞争性或非竞争性是未知的，所以不能够清楚的得知这些化合物对于抑制其它CCR1配体结合例如RANTES是否更加有效。
实施例4：CCR1功能性测定
CCR1是一种七次跨膜的G-蛋白连接的受体。由这些受体连接诱导的信号级联级联的标志是钙离子从细胞内贮库的类似于脉冲的释放。进行钙动员测试以确定候选MIP-Iα抑制性化合物是否也能阻断CCR1信号传递。为了使用，希望候选化合物能够抑制特异性配体结合以及发出传递。
响应MIP-Iα结合的钙离子释放通过细胞可渗透的INDO-1/AM显示剂测定，其在游离的而不是螯合的钙离子存在下发出荧光。CCR1-293或THP-1细胞用INDO-1加载，对响应加入MIP-Iα的钙离子释放进行测试。对于特异性对照，加入另外一种非CCR1结合趋化因子、缓激肽，其也是通过一种七次跨膜受体发出信号。没有化合物的情况下加入MIP-Iα时可以看到荧光信号脉冲。如果一种化合物特异性抑制CCR1-MIP-Iα信号传递，那么在加入MIP-Iα时将看不到任何信号脉冲，但在加入缓激肽时可看到一个脉冲。然而，如果一种化合物非特异性抑制信号传递，那么在加入MIP-Iα和缓激肽时将看不到任何脉冲。
如表.2所示，在测试的选择的化合物，CCX-469、CCX-541、CCX-1513和CCX-3493之中，只有CCX-469能够显著地并且特异地抑制CCR1的信号传递。CCX-541和CCX-1513对于钙离子水平具有非特异性作用，CCX-3493不能够影响信号传递，无论是MIP-Iα还是缓激肽诱导的。
表2.钙信号传递抑制
实施例5(推论)
趋化因子主要功能之一是其能够吸引WBCs至病原体侵入位点。为了证实化合物不仅能够如钙动员试验确定的抑制MIP-Iα结合和CCR1信号传递；而且能够抑制CCR1功能，进行了趋化性测试。THP-1髓细胞单核细胞白血病细胞，其与单核细胞相似，可用作MIP-Iα化学吸引的靶点。THP-1细胞位于微孔迁移室的上部的室中，而MIP-Iα和浓度增加的化合物加样于下部的室中。在无抑制剂时，THP-1细胞响应MIP-Iα趋化因子迁移至下部的室中；如果一种化合物抑制CCR1功能，那么大多数TIP-1细胞保持在上部的室中。
根据上文详述内容，提示了本领域技术人员本发明的许多变化形式，这些显而易见的变化包括在权利要求的保护范围之中。
参考文献
DeVries，M.E.，L.Ran，et al.(1999).“On the edge：the physiological andpathophysiological role of chemokines during inflammatory and immunologicalresponses.”Semin Immuuol 11(2)：95-104.
Fischer，F.R.，L.Santambrogio，et al.(2000).“Modulation of experimentalautoimmune encephalomyelitjs：effect of altered peptide ligand on chemokine andchemokine receptor expression.”J Neuroimmunol 110(1-2)：195-208.
Hesselgesser，J.，H.P.Ng，et al.(1998).“Identifioation and characterization of smallmoleoule functional antagonists of the CCR1 chemokine receptor.＂J Riol Chem273(25)；15687-92.
Izikson，L.，R.S.Klein，et al.(2000).“Resistaoce to experimental autoimmuneencephalomyelitis in mice lacking the CC chemokine receptor(CCR)2[In ProcessCitation].”I Exp Med 192(7)：1075-80.
Kennedy，K.J.and W.J.Karpus(1999).“Role of chemokine in the regulation ofTh1/Th2 and autoimmume encephalomyelitis.”J Clin Immunol 19(5)：273-9，
Liang，M.，C.Mallan，et al.(2000)Identification and charaoterization of a potent，selective，and orally active antagonist of the CC chomokine recoptor-1.”J Biol Chem 275(25)：19000-8.
Liang，M.，M.Roser，et al.(2000).“Species selectivity of a small moleculeantagonist for the CCR1 chemokine receptor.”Eur J Pharmacol 389(1)；41-9.
Ng，H.P.，K.May，et al.(1999).“Discovery of novel non-peptide CCR1 receptorantagonists.”J Med Chem 42(22)：4680-94.
Plater-Zyberk，C.，A.J.Hoogewerf，et al.(1997).“Effect of a CC chemokine receptorantagonist on collagen induced arthritis in DEA/1 mice，”Immunol Let 57(1-3)：117-20.
Rossi，D.and A.Zlotnik(2000).“The Biology of Chemokines and their Receptors.”Annu.Rev.Immunol.18(1)：217-242.
Rottman，J.B.，A.J.Slavin，et al，(2000)、“Leukocyte during onset ofexperimental allergic 
is CCR1 depcndent”Eur J Immunol30(8)：2372-7.
Claims (9)
1.一种组合物，包括药物可接受的载体和式(1)化合物：
其中：
n是2；
Y是氧或硫；
R1、R2、和R3分别独立地为氢或卤素。
2.根据权利要求1所述的组合物，其中所述化合物是一种式(2)化合物：
其中：
n是2；
Y是氧或硫；并且
R1、R2、和R3分别独立地为氢或卤素。
3.根据权利要求1的组合物，其中R1和R2是氢。
4.根据权利要求1的组合物，其中R3是卤素。
5.根据权利要求4的组合物，其中R3是氯或氟。
6.根据权利要求1的组合物，其中R3是氢。
7.一种组合物，包括药物可接受的载体和化合物CCX-469：
8.权利要求1或2的组合物在制备用于抑制趋化因子与CCR1受体结合的药物中的用途，该趋化因子是指MIP-1α或RANTES。
9.权利要求1或2的组合物在制备用于治疗炎性疾病的药物中的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/171,097 US6727241B2 (en) | 2002-06-12 | 2002-06-12 | Anti-inflammatory compositions and methods of use |
| US10/171,097 | 2002-06-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1658881A CN1658881A (zh) | 2005-08-24 |
| CN100506231C true CN100506231C (zh) | 2009-07-01 |
Family
ID=29732678
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038134136A Expired - Fee Related CN100506231C (zh) | 2002-06-12 | 2003-05-27 | 抗炎组合物及其制药用途 |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US6727241B2 (zh) |
| EP (1) | EP1534293A4 (zh) |
| JP (1) | JP4593271B2 (zh) |
| CN (1) | CN100506231C (zh) |
| AU (1) | AU2003234642B2 (zh) |
| CA (1) | CA2487331C (zh) |
| HK (1) | HK1081864A1 (zh) |
| MX (1) | MXPA04012389A (zh) |
| WO (1) | WO2003105857A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0301232D0 (sv) * | 2003-04-25 | 2003-04-25 | Astrazeneca Ab | Novel use |
| WO2005025556A2 (en) * | 2003-08-13 | 2005-03-24 | Oscient Pharmaceuticals | Antibiotic cycloalkyltetrahydroquinoline derivatives |
| EP2858648B1 (en) * | 2012-06-07 | 2018-08-22 | Beth Israel Deaconess Medical Center, Inc. | Methods and compositions for the inhibition of pin1 |
| US10351914B2 (en) | 2014-07-17 | 2019-07-16 | Beth Israel Deaconess Medical Center, Inc. | Biomarkers for Pin1-associated disorders |
| US10548864B2 (en) | 2015-03-12 | 2020-02-04 | Beth Israel Deaconess Medical Center, Inc. | Enhanced ATRA-related compounds for the treatment of proliferative diseases, autoimmune diseases, and addiction conditions |
| IL251949A0 (en) * | 2017-04-26 | 2017-07-31 | Medical Res Infrastructure & Health Services Fund Tel Aviv Medical Ct | Small organic molecules for use in the treatment of neuro-inflammatory diseases |
| US20210261537A1 (en) * | 2018-06-07 | 2021-08-26 | Disarm Therapeutics, Inc. | Inhibitors of sarm1 |
| JP7212781B2 (ja) | 2018-12-19 | 2023-01-25 | ディスアーム セラピューティクス， インコーポレイテッド | 神経保護剤と組み合わせたｓａｒｍ１の阻害剤 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4166452A (en) | 1976-05-03 | 1979-09-04 | Generales Constantine D J Jr | Apparatus for testing human responses to stimuli |
| US4256108A (en) | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
| JPS5520743A (en) * | 1978-08-01 | 1980-02-14 | Toray Ind Inc | Alpha-substituted amino-epsilon-caprolactam |
| US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
| US5541213A (en) * | 1993-06-24 | 1996-07-30 | Eisai Co., Ltd. | Propenoic acid derivatives diazole propenoic acid compounds which have useful pharmaceutical utility |
| WO1996029307A1 (fr) * | 1995-03-23 | 1996-09-26 | Japan Tobacco Inc. | Composes de diphenylmethyle-azetidinone et inhibiteur d'elastase |
| JPH09301972A (ja) * | 1996-05-10 | 1997-11-25 | Dainippon Pharmaceut Co Ltd | Ｎ−（１−置換−アザシクロアルカン−３−イル）カルボキサミド誘導体及びそれを含有する医薬組成物 |
| DE69709647T2 (de) | 1996-05-20 | 2002-11-07 | Dupont Pharmaceuticals Research Laboratories, Inc. | Cyclischer diarylalkyl diaminederivate als antogoniste von chemokinerezeptoren |
| US6207665B1 (en) | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
| DE69928226T8 (de) | 1998-01-21 | 2006-10-19 | Millennium Pharmaceuticals, Inc., Cambridge | Chemokin rezeptor antagonisten und verwendung |
| WO1999037619A1 (en) | 1998-01-21 | 1999-07-29 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| AP1462A (en) * | 1998-01-29 | 2005-09-02 | Aventis Pharma Inc | Method for preparing an n-[(aliphatic or aromatic)carbonyl]-2- aminoacetamide compound and a cyclyzed compound. |
| US6197750B1 (en) * | 1998-07-02 | 2001-03-06 | Idun Pharmaceuticals, Inc. | C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
| WO2000044408A2 (en) * | 1999-01-29 | 2000-08-03 | Millennium Pharmaceuticals, Inc. | Method of treating demyelinating inflammatory disease using ccr1 antagonists |
| EP1152752A1 (en) * | 1999-01-29 | 2001-11-14 | Millennium Pharmaceuticals, Inc. | Methods for preventing graft rejection and ischemia-reperfusion injury |
| WO2000053600A1 (fr) | 1999-03-11 | 2000-09-14 | Banyu Pharmaceutical Co., Ltd. | Derives piperidiniques |
-
2002
- 2002-06-12 US US10/171,097 patent/US6727241B2/en not_active Expired - Lifetime
-
2003
- 2003-05-27 CN CNB038134136A patent/CN100506231C/zh not_active Expired - Fee Related
- 2003-05-27 EP EP03729143A patent/EP1534293A4/en not_active Withdrawn
- 2003-05-27 MX MXPA04012389A patent/MXPA04012389A/es active IP Right Grant
- 2003-05-27 AU AU2003234642A patent/AU2003234642B2/en not_active Ceased
- 2003-05-27 JP JP2004512760A patent/JP4593271B2/ja not_active Expired - Fee Related
- 2003-05-27 CA CA002487331A patent/CA2487331C/en not_active Expired - Fee Related
- 2003-05-27 WO PCT/US2003/016558 patent/WO2003105857A1/en active Application Filing
- 2003-05-30 US US10/536,071 patent/US20070072875A1/en not_active Abandoned
-
2006
- 2006-02-20 HK HK06102229.3A patent/HK1081864A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US20030236249A1 (en) | 2003-12-25 |
| WO2003105857A1 (en) | 2003-12-24 |
| MXPA04012389A (es) | 2005-06-22 |
| EP1534293A4 (en) | 2009-09-16 |
| HK1081864A1 (en) | 2006-05-26 |
| CA2487331C (en) | 2008-08-12 |
| JP4593271B2 (ja) | 2010-12-08 |
| EP1534293A1 (en) | 2005-06-01 |
| CN1658881A (zh) | 2005-08-24 |
| AU2003234642A1 (en) | 2003-12-31 |
| JP2005538060A (ja) | 2005-12-15 |
| US20070072875A1 (en) | 2007-03-29 |
| CA2487331A1 (en) | 2003-12-24 |
| AU2003234642B2 (en) | 2009-06-04 |
| US6727241B2 (en) | 2004-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Scott et al. | Discovery and SAR of novel 2, 3‐dihydroimidazo [1, 2‐c] quinazoline PI3K inhibitors: identification of copanlisib (BAY 80‐6946) | |
| Nozhat et al. | PI3K/AKT pathway and its mediators in thyroid carcinomas | |
| US20230129598A1 (en) | Methods of treating estrogen receptor-associated diseases | |
| US7262204B2 (en) | Modulation of CCR4 function | |
| US6900219B2 (en) | ABCA-1 elevating compounds | |
| Intagliata et al. | Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6, 7-Dimethoxy-3, 4-dihydroisoquinolin-2 (1 H)-yl) butyl)-3-methyl-1 H-benzo [d] imidazol-2 (3 H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo | |
| CN109498812A (zh) | Hsp90组合疗法 | |
| CA2598409A1 (en) | Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation | |
| Patel et al. | Discovery of orally efficacious phosphoinositide 3-kinase δ inhibitors with improved metabolic stability | |
| CN1607952A (zh) | 包含多官能磷酸二酯酶抑制剂和腺苷吸收抑制剂的药物组合物 | |
| Boss et al. | Discovery and characterization of ACT‐451840: an antimalarial drug with a novel mechanism of action | |
| KR102096557B1 (ko) | 통증 치료용 약학 조성물 | |
| CN100506231C (zh) | 抗炎组合物及其制药用途 | |
| US20020132836A1 (en) | Compounds and methods for modulating CCR4 function | |
| KR20040007485A (ko) | 알레르기성 질환과 같은 비만세포계 질병에 대한ｎ-페닐-2-피리미딘아민의 용도 | |
| CN100457111C (zh) | 星孢素衍生物制备药物的用途 | |
| AU2002307140A1 (en) | Use of N-Phenyl-2-Pyrimidineamine Derivatives against mast cell-based diseases like allergic disorders | |
| EP2352501B1 (en) | Compounds for use in the treatment of osteoporosis | |
| EP2887940A2 (en) | Inhibitors of crl4 ubiquitin ligase and uses thereof | |
| JP2007513967A (ja) | 変異レセプターチロシンキナーゼが駆動する細胞増殖性疾患の処置において使用するための組成物 | |
| CN106243096B (zh) | 三环类药物的新用途 | |
| Gleeson et al. | Neurochemical effects of 5-HT1 receptor ligands in pigeons | |
| US20120277246A1 (en) | Use of N-Phenyl-2-pyrimidineamine Derivatives Against Mast Cell-based Diseases Like Allergic Disorders | |
| CA2517308A1 (en) | Tailored treatment suitable for different forms of mastocytosis | |
| JP6748704B2 (ja) | 抗癌治療剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1081864 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1081864 Country of ref document: HK |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090701 Termination date: 20130527 |