NZ618110B2 - Beta - hairpin peptidomimetics as cxc4 antagonists - Google Patents
Beta - hairpin peptidomimetics as cxc4 antagonists Download PDFInfo
- Publication number
- NZ618110B2 NZ618110B2 NZ618110A NZ61811012A NZ618110B2 NZ 618110 B2 NZ618110 B2 NZ 618110B2 NZ 618110 A NZ618110 A NZ 618110A NZ 61811012 A NZ61811012 A NZ 61811012A NZ 618110 B2 NZ618110 B2 NZ 618110B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- pharmaceutically acceptable
- acceptable salt
- amino acid
- compound
- Prior art date
Links
- 230000003042 antagnostic Effects 0.000 title claims description 9
- 239000000816 peptidomimetic Substances 0.000 title abstract description 37
- 239000005557 antagonist Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 31
- 210000000130 stem cell Anatomy 0.000 claims abstract description 26
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 12
- 208000005721 HIV Infections Diseases 0.000 claims abstract description 11
- 108010061299 CXCR4 Receptors Proteins 0.000 claims abstract description 10
- 102000012000 CXCR4 Receptors Human genes 0.000 claims abstract description 10
- 230000001404 mediated Effects 0.000 claims abstract description 9
- 239000011886 peripheral blood Substances 0.000 claims abstract description 8
- 230000017423 tissue regeneration Effects 0.000 claims abstract description 8
- 206010062016 Immunosuppression Diseases 0.000 claims abstract description 7
- 101710027907 cys-11 Proteins 0.000 claims abstract description 7
- 230000001506 immunosuppresive Effects 0.000 claims abstract description 7
- 230000003612 virological Effects 0.000 claims abstract description 7
- 238000002617 apheresis Methods 0.000 claims abstract description 6
- 206010021425 Immune system disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 56
- -1 N-protected amino Chemical group 0.000 claims description 34
- 239000007787 solid Substances 0.000 claims description 31
- 102100002212 CXCR4 Human genes 0.000 claims description 29
- 101710003734 CXCR4 Proteins 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 28
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
- 238000005859 coupling reaction Methods 0.000 claims description 21
- 230000001808 coupling Effects 0.000 claims description 19
- 238000010168 coupling process Methods 0.000 claims description 19
- 150000001413 amino acids Chemical class 0.000 claims description 17
- 125000000660 D-proline group Chemical group [H]N1[C@](C(=O)[*])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 13
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000002849 D-tyrosine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 10
- 230000000875 corresponding Effects 0.000 claims description 9
- 125000000524 functional group Chemical group 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- 230000001093 anti-cancer Effects 0.000 claims description 4
- 230000003110 anti-inflammatory Effects 0.000 claims description 4
- 230000000699 topical Effects 0.000 claims description 4
- 150000008574 D-amino acids Chemical group 0.000 claims description 3
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 claims description 3
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- CAILUIWIXZDVSZ-SNVBAGLBSA-N (2R)-2-azaniumyl-2-(4-methoxyphenyl)propanoate Chemical compound COC1=CC=C([C@@](C)(N)C(O)=O)C=C1 CAILUIWIXZDVSZ-SNVBAGLBSA-N 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 230000001483 mobilizing Effects 0.000 claims 3
- CAILUIWIXZDVSZ-JTQLQIEISA-N (2S)-2-azaniumyl-2-(4-methoxyphenyl)propanoate Chemical compound COC1=CC=C([C@](C)(N)C(O)=O)C=C1 CAILUIWIXZDVSZ-JTQLQIEISA-N 0.000 claims 1
- OGNSCSPNOLGXSM-VKHMYHEASA-N L-2,4-diaminobutyric acid Chemical group NCC[C@H](N)C(O)=O OGNSCSPNOLGXSM-VKHMYHEASA-N 0.000 claims 1
- 150000008575 L-amino acids Chemical group 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000011505 plaster Substances 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 abstract description 28
- 239000003795 chemical substances by application Substances 0.000 abstract description 10
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 230000002349 favourable Effects 0.000 abstract description 3
- 229920005989 resin Polymers 0.000 description 50
- 239000011347 resin Substances 0.000 description 50
- 210000004027 cells Anatomy 0.000 description 36
- 239000000203 mixture Substances 0.000 description 34
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 235000001014 amino acid Nutrition 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- 125000005647 linker group Chemical group 0.000 description 18
- 210000002381 Plasma Anatomy 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000010511 deprotection reaction Methods 0.000 description 13
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 229940079593 drugs Drugs 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 235000019253 formic acid Nutrition 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 230000002194 synthesizing Effects 0.000 description 10
- 210000004369 Blood Anatomy 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 238000005755 formation reaction Methods 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 239000004793 Polystyrene Substances 0.000 description 8
- 239000002609 media Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229940024606 Amino Acids Drugs 0.000 description 7
- 229940019746 Antifibrinolytic amino acids Drugs 0.000 description 7
- 229940021015 I.V. solution additive Amino Acids Drugs 0.000 description 7
- 150000002019 disulfides Chemical class 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 230000001225 therapeutic Effects 0.000 description 7
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 6
- 108010012236 Chemokines Proteins 0.000 description 6
- 238000004166 bioassay Methods 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 102100014691 CXCL12 Human genes 0.000 description 5
- 101710043128 CXCL12 Proteins 0.000 description 5
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 5
- 206010024324 Leukaemias Diseases 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 238000011068 load Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 229920002223 polystyrene Polymers 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- RHQDFWAXVIIEBN-UHFFFAOYSA-N 2,2,2-trifluoroethyl alcohol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 4
- 102000001189 Cyclic Peptides Human genes 0.000 description 4
- 108010069514 Cyclic Peptides Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 230000003399 chemotactic Effects 0.000 description 4
- 230000035605 chemotaxis Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000002949 hemolytic Effects 0.000 description 4
- 230000000051 modifying Effects 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 230000002459 sustained Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 210000000988 Bone and Bones Anatomy 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 229940116441 DIVINYLBENZENE Drugs 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 210000003743 Erythrocytes Anatomy 0.000 description 3
- 206010018910 Haemolysis Diseases 0.000 description 3
- LJQLCJWAZJINEB-UHFFFAOYSA-N Hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F LJQLCJWAZJINEB-UHFFFAOYSA-N 0.000 description 3
- 206010022114 Injury Diseases 0.000 description 3
- 208000006897 Interstitial Lung Disease Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 206010027476 Metastasis Diseases 0.000 description 3
- 206010025310 Other lymphomas Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 229940035295 Ting Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 210000003995 blood forming stem cell Anatomy 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 201000009910 diseases by infectious agent Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000002757 inflammatory Effects 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 201000009251 multiple myeloma Diseases 0.000 description 3
- 230000000275 pharmacokinetic Effects 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- 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 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-Hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 2
- 206010000880 Acute myeloid leukaemia Diseases 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N Adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 206010001897 Alzheimer's disease Diseases 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 208000006673 Asthma Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000001185 Bone Marrow Anatomy 0.000 description 2
- 102100008428 CCL2 Human genes 0.000 description 2
- 102100016492 CD34 Human genes 0.000 description 2
- 108060001251 CD34 Proteins 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 230000037250 Clearance Effects 0.000 description 2
- 230000035700 Clearance Rate Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 208000009745 Eye Disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 210000003958 Hematopoietic Stem Cells Anatomy 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N Interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 229940096397 Interleukin-8 Drugs 0.000 description 2
- 206010061256 Ischaemic stroke Diseases 0.000 description 2
- 210000003734 Kidney Anatomy 0.000 description 2
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- 210000003141 Lower Extremity Anatomy 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 206010025650 Malignant melanoma Diseases 0.000 description 2
- 210000002901 Mesenchymal Stem Cells Anatomy 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000010125 Myocardial Infarction Diseases 0.000 description 2
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 2
- 206010034576 Peripheral ischaemia Diseases 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N Pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 230000036660 Plasma protein binding Effects 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 210000003324 RBC Anatomy 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N Suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- ZHHGTMQHUWDEJF-UHFFFAOYSA-N [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=C(Cl)C=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 ZHHGTMQHUWDEJF-UHFFFAOYSA-N 0.000 description 2
- GBGVQFJZGHBZMC-UHFFFAOYSA-N [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=C(Cl)C=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 GBGVQFJZGHBZMC-UHFFFAOYSA-N 0.000 description 2
- JKEKMBGUVUKMQB-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JKEKMBGUVUKMQB-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 2
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000006474 brain ischemia Diseases 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000001889 chemoattractant Effects 0.000 description 2
- 239000002975 chemoattractant Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000035512 clearance Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 230000001809 detectable Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic Effects 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 200000000018 inflammatory disease Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000001665 lethal Effects 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 201000002818 limb ischemia Diseases 0.000 description 2
- 230000002934 lysing Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000002685 pulmonary Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000003638 reducing agent Substances 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000001105 regulatory Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 1
- LUGFCMICCJNLBC-VWLOTQADSA-N (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCN(C(C)C)C(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 LUGFCMICCJNLBC-VWLOTQADSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (E)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ORHBGEQYIZTYHV-UHFFFAOYSA-N 1,1-di(propan-2-yl)urea Chemical compound CC(C)N(C(C)C)C(N)=O ORHBGEQYIZTYHV-UHFFFAOYSA-N 0.000 description 1
- NHEGCUSBUWGOQM-UHFFFAOYSA-N 1-[chloro(pyrrolidin-1-ium-1-ylidene)methyl]pyrrolidine;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCC[N+]1=C(Cl)N1CCCC1 NHEGCUSBUWGOQM-UHFFFAOYSA-N 0.000 description 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- OOWSDKUFKGVADH-UHFFFAOYSA-N 1-diphenylphosphoryloxy-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 OOWSDKUFKGVADH-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N 2-mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JDQDSEVNMTYMOC-UHFFFAOYSA-N 3-methylbenzenesulfonic acid Chemical compound CC1=CC=CC(S(O)(=O)=O)=C1 JDQDSEVNMTYMOC-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-Aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- QHZHLPBJFZQTIP-UHFFFAOYSA-N 4-[4-(hydroxymethyl)-2-methoxyphenoxy]butanoic acid Chemical compound COC1=CC(CO)=CC=C1OCCCC(O)=O QHZHLPBJFZQTIP-UHFFFAOYSA-N 0.000 description 1
- HXOYWJCDYVODON-UHFFFAOYSA-N 4-[4-(hydroxymethyl)-3-methoxyphenoxy]butanoic acid Chemical compound COC1=CC(OCCCC(O)=O)=CC=C1CO HXOYWJCDYVODON-UHFFFAOYSA-N 0.000 description 1
- 229940046932 4-aminosalicylic acid Drugs 0.000 description 1
- JKUDJCOGFRIXGQ-UHFFFAOYSA-N 9H-fluoren-9-ylmethyl 2-amino-4-[2-[[4-[amino(phenyl)methyl]phenyl]methyl]hydrazinyl]-2-(2,4-dimethoxyphenyl)-4-oxo-3-phenoxybutanoate Chemical compound COC1=CC(OC)=CC=C1C(N)(C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(C(=O)NNCC=1C=CC(=CC=1)C(N)C=1C=CC=CC=1)OC1=CC=CC=C1 JKUDJCOGFRIXGQ-UHFFFAOYSA-N 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 206010000891 Acute myocardial infarction Diseases 0.000 description 1
- 206010064930 Age-related macular degeneration Diseases 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 108009000283 Allograft Rejection Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-N Armstrong's acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N Azelaic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- 210000003719 B-Lymphocytes Anatomy 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 210000000601 Blood Cells Anatomy 0.000 description 1
- 229940098773 Bovine Serum Albumin Drugs 0.000 description 1
- 108091003117 Bovine Serum Albumin Proteins 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 102100019487 CCL11 Human genes 0.000 description 1
- 101700006000 CCL2 Proteins 0.000 description 1
- 102100012080 CCR5 Human genes 0.000 description 1
- 101700043583 CCR5 Proteins 0.000 description 1
- 229940121384 CXC chemokine receptor type 4 (CXCR4) antagonists Drugs 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 210000000845 Cartilage Anatomy 0.000 description 1
- 210000003467 Cheek Anatomy 0.000 description 1
- 108010082548 Chemokine CCL11 Proteins 0.000 description 1
- 108010055292 Chemokine CCL2 Proteins 0.000 description 1
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N Citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N Cyclamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 1
- 206010012601 Diabetes mellitus Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N Dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 210000001956 EPC Anatomy 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 210000002889 Endothelial Cells Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N Ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 241000276438 Gadus morhua Species 0.000 description 1
- 206010017758 Gastric cancer Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000005017 Glioblastoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- 229960002743 Glutamine Drugs 0.000 description 1
- 206010018651 Graft versus host disease Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 230000036499 Half live Effects 0.000 description 1
- 239000012593 Hanks’ Balanced Salt Solution Substances 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 210000004969 Inflammatory Cells Anatomy 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N Isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 229940119837 Isopropyl Alcohol Drugs 0.000 description 1
- 241000229754 Iva xanthiifolia Species 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N Lauric acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 description 1
- 208000009856 Lung Disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 238000003222 MTT reduction assay Methods 0.000 description 1
- 208000002780 Macular Degeneration Diseases 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 206010028417 Myasthenia gravis Diseases 0.000 description 1
- 208000005927 Myosarcoma Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N N'-amino-N-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 125000000534 N(2)-L-lysino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C([H])([H])C(C([H])([H])N([H])[H])([H])[H] 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N Ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 229960003104 Ornithine Drugs 0.000 description 1
- 210000002997 Osteoclasts Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 101710043203 P23p89 Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 229960003531 Phenolsulfonphthalein Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N Phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 230000036823 Plasma Levels Effects 0.000 description 1
- 230000036908 Plasma Stability Effects 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N Plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 229960002169 Plerixafor Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000240376 Proteus anguinus Species 0.000 description 1
- 206010037162 Psoriatic arthropathy Diseases 0.000 description 1
- 229940100486 RICE STARCH Drugs 0.000 description 1
- 239000007759 RPMI Media 1640 Substances 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010038932 Retinopathy Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 206010040767 Sjogren's syndrome Diseases 0.000 description 1
- 208000006641 Skin Disease Diseases 0.000 description 1
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- 210000002536 Stromal Cells Anatomy 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N Tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 229940100445 WHEAT STARCH Drugs 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 1
- AUPDFAPCZZXFMX-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 AUPDFAPCZZXFMX-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance 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
- CDXSJGDDABYYJV-UHFFFAOYSA-N acetic acid;ethanol Chemical compound CCO.CC(O)=O CDXSJGDDABYYJV-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 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
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000007854 aminals Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 230000002491 angiogenic Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001857 anti-mycotic Effects 0.000 description 1
- 230000000798 anti-retroviral Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960002255 azelaic acid Drugs 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 210000004271 bone marrow stromal cells Anatomy 0.000 description 1
- 201000005216 brain cancer Diseases 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000006143 cell culture media Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229920002083 cellular DNA Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000005591 charge neutralization Effects 0.000 description 1
- 239000002576 chemokine receptor CXCR4 antagonist Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 235000019516 cod Nutrition 0.000 description 1
- 230000001332 colony forming Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000001804 emulsifying Effects 0.000 description 1
- 230000003511 endothelial Effects 0.000 description 1
- 201000009580 eosinophilic pneumonia Diseases 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- SIVVHUQWDOGLJN-UHFFFAOYSA-N ethylsulfamic acid Chemical group CCNS(O)(=O)=O SIVVHUQWDOGLJN-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000003260 fluorescence intensity Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002518 glial Effects 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 230000003394 haemopoietic Effects 0.000 description 1
- 230000002489 hematologic Effects 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 238000002665 ion therapy Methods 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 230000000155 isotopic Effects 0.000 description 1
- 230000000366 juvenile Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012577 media supplement Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N methylsulfanylbenzene Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 201000002077 muscle cancer Diseases 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 230000002148 osteoclast Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 108010056903 polyphemusin II Proteins 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000770 pro-inflamatory Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- HLIBNTOXKQCYMV-UHFFFAOYSA-N propylsulfamic acid Chemical compound CCCNS(O)(=O)=O HLIBNTOXKQCYMV-UHFFFAOYSA-N 0.000 description 1
- 238000001711 protein immunostaining Methods 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 201000001263 psoriatic arthritis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000003252 repetitive Effects 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
Abstract
Hairpin peptidomimetics of the general formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5- Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Xaa13-Xaa14-DPro15-Pro16-), disulfide bond between Cys4 and Cys11, and pharmaceutically acceptable salts thereof, with Xaa3, Xaa7, Xaa8, Xaa13 and Xaa14 being amino acid residues of certain types which are defined in the specification, have favorable pharmacological properties and can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stem cells and/or as agents to induce mobilization of stem cells to regulate tissue repair. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy. f certain types which are defined in the specification, have favorable pharmacological properties and can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stem cells and/or as agents to induce mobilization of stem cells to regulate tissue repair. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.
Description
BETA-HAIRPIN PEPTIDOMIMETICS AS CXC4 ANTAGONISTS
The present invention provides B-hairpin peptidomimetics which are having CXCR4
antagonizing activity and are embraced by the general disclosure of, but not
specifically disclosed in W02004/096840 A1.
The B-hairpin peptidomimetics of the invention are cyclo(—Tyr1-HisZ-Xaas-Cys4-Ser5-
aa7-Xaa8-Arg9-Tyrlo-Cysll-Tyrlz-Xaa13-Xaa14-DPr015-Pr016-), disulfide bond
between Cys4 and Cysll, and pharmaceutically acceptable salts thereof, with Xaa3
being Ala, Tyr or Tyr(Me) as described herein below, Xaa7 being DTyr, DTyr(Me) as
described herein below or DPro, Xaa8 being Dab or Orn(iPr) as described herein below,
Xaa13 being Gln or Glu, and Xaa14 being Lys(iPr), as described herein below.
In addition, the present invention provides an efficient synthetic s by which
these compounds can, if desired, be made in el library-format. These B-hairpin
peptidomimetics have favorable cological properties and, in addition, show
suitable plasma protein binding and appropriate clearance rates. Therefore they can
be used as active ients in low amounts for all kind of drug formulations, in
particular extended release drug formulations.
Many medically icant biological ses are mediated by signal transduction
that involves chemokines and their receptors in general and stromal derived factor 1
(SDF-l/ CXCL12) and its receptor CXCR4 in particular.
CXCR4 and its ligand SDF-l are involved in trafficking of B-cells, poietic stem
cells (HSC) and hematopoietic progenitor cells (HPC). For instance, CXCR4 is expressed
on CD34+ cells and has been implicated in the process of CD34+ cell migration and
homing (S.M. Watt, S.P. Forde, Vox nis 2008, 94, 18-32). It has also been shown
that the CXCR4 receptor plays an important role in the release of stem and progenitor
cells from the bone marrow to the eral blood (L.M. Pelus, S. Fukuda, Leukemia
2008, 22, 466-473). This activity of CXCR4 could be very important for efficient
apheresis collections of peripheral blood stem cells. Autologous peripheral blood cells
provide a rapid and sustained hematopoietic recovery following auto-transplantation
after the administration of high-dose chemotherapy or radiotherapy in patients with
haematological ancies and solid tumors (W.C. Liles et al., Blood 2003, 102,
2728-2730).
Recently, it has been demonstrated that SDF-l is locally up-regulated in animal
models of injury including focal ischemic stroke, global cerebral ischemia, myocardial
infarction and hind limb ischemia as well as being involved in recovery after
peripheral ischemia or following injury to the liver, kidney or lung (A.E. Ting, R.W.
Mays, M.R. Frey, W. Van’t Hof, S. Medicetty, R. Deans, Critical s in
Oncology/Hematology 2008, 65, 81-93 and literature cited herein; F. Lin, K. , L.
Li, L. Hood, W.G. Couser, S.J. and et al., J. Am. Soc. Nephrol. 2003, 14, 1188-
1199; CC. Dos Santos, Intensive Care Med. 2008, 34, 619-630). These results suggest
that SDF-l may be a chemoattractant for CXCR4-positive stem cells for tissue and
organ repair/regeneration (M.Z. Ratajczak, M. Kucia, R. Reca, M. Majka, A. Janowska-
Wieczorek, J. zak, Leukemia 2004, 18, 29-40). Therefore, modulating the
SDF-l/CXCR4 axis by CXCR4 inhibitors should result in a significant therapeutic t
by using released stem cells to regulate tissue repair.
More recently, it has been shown that disrupting the CXCR4/SDF-1 axis by CXCR4
inhibitors plays a crucial role in differential mobilization of progenitor cells like HPCs,
endothelial (EPCs) and stromal progenitor cells (SPCs) from the bone marrow
(S.C. Pitchford, R.C. Furze, C.P. Jones, A.M. Wegner, S.M. Rankin, Cell Stem Cell 2009,
4, 62). In addition, bone -derived CXCR4+ Very Small Embryonic-Like Stem
Cells ) were mobilized in patients with acute myocardial infarction ting a
hypothetical reparatory mechanism (W. Wojakowski, M. Tendra, M. Kucia, E. Zuba-
Surma, E. Paczkowska, J. Ciosek, M. Halasa, M. Krol, M. Kazmierski, P. n,
A. Ochala, J. Ratajczak, B. Machalinski, M.Z. zak, J. Am. Coll. Cardiol. 2009, 53,
1). These findings may be exploited to e efficacious stem cell therapy for tissue
regeneration.
Mesenchymal stem cells (MSC) are nonhematopoietic progenitor cells having the
capability of differentiating into tissues such as bone and cartilage (DJ. Prockop,
Science 1997, 276, 71). As a small tion of MSCs strongly expresses functionally
active CXCR4, modulation of the CXCR4/SDF-1 axis may mediate specific migration
and homing of these cells (R.F. Wynn, C.A. Hart, C. Corradi-Perini, L. O’Neill, C.A.
Evans, J.E. Wraith, L.J. im, |. Bellantuono, Blood 2004, 104, 2643).
There is increasing ce suggesting that chemokines in general and the
SDF-l/CXCR4 interaction in particular play a pivotal role in angiogenesis. Chemokines
induce angiogenesis directly by binding their cognate receptors on endothelial cells or
indirectly by promoting inflammatory cell infiltrates, which deliver other angiogenic
stimuli. A number of proinflammatory chemokines including interleukin 8 (IL-8),
growth-regulated oncogene, l cell—derived factor 1 ), monocyte
chemotactic protein 1(MCP-1), eotaxin 1, and I-309 have been shown to act as direct
inducers of angiogenesis (X. Chen, J.A. r, T.G. McCloud, A. Loehfelm, L. Yang,
H.F. Dong, O.Y. Chertov, R. Salcedo, JJ. Oppenheim, O.M. Howard. Clin. Cancer Res.
2003, 9(8), 3115-3123; R. Salcedo, JJ. Oppenheim, Microcirculation 2003, (3-4), 359-
370).
ly obtained results show that the CXCR4 receptor is involved in the
chemotactic activity of cancer cells, such as breast cancer metastasis or in asis
of ovarian cancer (A. Muller, B. Homey, H. Soto, N. Ge, D. Catron, M.E. Buchanan, T.
Mc Clanahan, E. Murphey, W. Yuan, S.N. Wagner, J.L. Barrera, A. Mohar, E.
Verastegui, A. Zlotnik, Nature 2001, 50, 410; J.M. Hall, K.S. Korach, Molecular
Endocrinology 2003, 17, 792-803), Non-Hodgin’s Lymphoma (F. Bertolini, C.
Dell’Agnola, P. Manusco, C. Rabascio, A. Burlini, S. iroli, A. Gobbi, G. Pruneri,
G. Martinelli, Cancer Research 2002, 62, 112), or lung cancer (T. Kijima, G.
Maulik, P.C. Ma, E.V. Tibaldi, R.E. Turner, B. s, M. Sattler, B.E. Johnson, R. Salgia,
Cancer Research 2002, 62, 311), melanoma, prostate cancer, kidney cancer,
neuroblastomia, pancreatic cancer, multiple myeloma, chronic lymphocytic leukemia,
hepatocellular carcinoma, colorectal carcinoma, endometrial cancer and germ cell
tumor (H. Tamamura et al., FEBS Letters 2003, 550, 79-83, cited ref.; Z. Wang, Q. Ma,
Q. Liu, H.Yu, L. Zhao, S. Shen, J. Yao, British Journal of Cancer 2008, 99, 1695; B. Sung,
S. i, K.S. Ahn, Y. Mastuo, T. Yi, S. Guha, M. Liu, B. Aggarwal, Cancer Res. 2008,
68, 8938; H. Liu, Z. Pan, A. Li, S. Fu, Y. Lei, H. Sun, M. Wu, W. Zhou, Cellular anal
Molecular Immunology, 2008, 5, 373; C. Rubie, O. Kollmar, V.O. Frick, M. , B.
Brittner, S. Graber, M.K. Schilling, Scandinavian Journal oflmmunology 2008, 68, 635;
S. Gelmini, M. Mangoni, F. Castiglioe, C. Beltrami, A. Pieralli, K.L. Andersson, M.
Fambrini, G.|. Taddie, M. Serio, C. Orlando, Clin. Exp. Metastasis 2009, 26, 261; D.C.
Gilbert, |. Chandler, A. re, N.C. Goddard, R. Gabe, R.A. Huddart, J. Shipley, J.
Pathol. 2009, 217, 94). Blocking the chemotactic activity with a CXCR4 inhibitor
should stop the migration of cancer cells and thus metastasis.
CXCR4 has also been implicated in the growth and proliferation of solid tumors and
leukemia/lymphoma. It was shown that activation of the CXCR4 or was critical
for the growth of both malignant neuronal and glial tumors. er, systemic
administration of the CXCR4 antagonist AMD3100 inhibits growth of intracranial
glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing
the proliferation of tumor cells (J.B. Rubin, A.L Kung, R.S Klein, J.A. Chan, Y. Sun, K.
t, M.W. Kieran, A.D. Luster, R.A. Segal, Proc Natl Acad Sci U S A. 2003,
100(23),13513-13518; S. Barbero, R. Bonavia, A. Bajetto, C. Porcile, P. Pirani, J.L.
Ravetti, G.L. Zona, R. Spaziante, T. Florio, G. Schettini, Cancer Res. 2003, 63(8), 1969-
1974; T. Kijima, G. Maulik, P.C. Ma, E.V. Tibaldi, R.E. Turner, B. Rollins, M. Sattler,
B.E. Johnson, R. Salgia. Cancer Res. 2002, , 6304-6311). CXCR4 inhibitors also
showed promising in vitro and in vivo cies in breast cancer, small cell lung
cancer, pancreatic cancer, gastric cancer, colorectal , malignant melanoma,
ovarian cancer, myo-sarcoma, prostate cancer as well as chronic lymphocytic
leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, multiple
myeloma and dgkin’s lymphoma (J.A. , A. Peled, Leukemia 2009, 23, 43-
52 and literature cited ).
It is well established that chemokines are involved in a number of inflammatory
pathologies and some of them show a pivotal role in the modulation of osteoclast
pment. Immunostaining for SDF-l (CXCL12) on synovial and bone tissue
biopsies from both rheumatoid arthritis (RA) and osteoarthritis (OA) samples have
ed strong increases in the expression levels of chemokines under inflammatory
conditions (F. Grassi, S. Cristino, S. Toneguzzi, A. Piacentini, A. Facchini, G. Lisignoli, J.
Cell Physiol. 2004; , 244-251). It seems likely that the CXCR4 receptor plays an
important role in inflammatory diseases such as rheumatoid arthritis, asthma,
multiple sclerosis, Alzheimer’s disease, Parkinson’s e, sclerosis, or eye
diseases such as diabetic retinopathy and age d r degeneration (K.R.
i et al., Scandinavian Journal of Immunology 2003, 57, 192-198; J.A. Gonzalo, J.
Immunol. 2000, 165, 499-508; S. Hatse et al., FEBS Letters 2002, 527, 255-262 and
cited references, A.T. Weeraratna, A. Kalehua, |. DeLeon, D. Bertak, G. Maher, M.S.
Wade, A. Lustig, K.G. Becker, W. Wood, D.G. Walker, T.G. Beach, D.D. Taub, Exp. Cell
Res. 2007, 313, 450; M. Shimoji, F. Pagan, E.B. Healton, |. Mocchetti, Neurotox. Res.
2009, 16, 318; A. Zernecke, E. Shagdarsuren, C. Weber, Arteriosc/er. Thromb. Vasc.
Biol. 2008, 28, 1897; R. Lima e Silva, J. Shen, S.F. Hackett, S. Kachi, H. Akiyama et al.,
FASEB 2007, 21, 3219). The mediation of recruitment of immune cells to sites of
inflammation should be stopped by a CXCR4 inhibitor.
To date the available therapies for the treatment of HIV infections have been leading
to a remarkable improvement in ms and recovery from disease in infected
people. Although the highly active anti-retroviral therapy ) which involves a
combination of reverse transcriptase/ protease-inhibitor has dramatically improved
the clinical treatment of individuals with AIDS or HIV infection, there have still
remained several serious problems including multi drug resistance, significant adverse
2012/060763
effects and high costs. Particularly desired are anti-HIV agents that block the HIV
ion at an early stage ofthe infection, such as the viral entry. It has recently been
recognized that for efficient entry into target cells, human immunodeficiency viruses
require the chemokine receptors CCR5 and CXCR4 as well as the primary receptor
CD4 (N. Levy, Engl. J. Med. 1996, 335, 1528-1530). Accordingly, an agent which could
block the CXCR4 chemokine receptors should prevent infections in healthy individuals
and slow or halt viral progression in infected patients (J. Cohen, Science 1997, 275,
1261-1264).
Among the different types of CXCR4 inhibitors (M. Schwarz, T.N.C. Wells, A.E.|.
Proudfoot, Receptors and Channels 2001, 7, 417-428; Y. Lavrovsky, Y.A. |vanenkov,
K.V. Balakin, D.A. Medvedewa, P.V. |vachtchenko, Mini Rev. Med. Chem. 2008, 11,
087), one emerging class is based on naturally occurring cationic peptide
analogues derived from Polyphemusin II which have an rallel B-sheet structure,
and a B-hairpin that is maintained by two disulfide bridges (H. Nakashima, M.
Masuda, T. Murakami, Y. Koyanagi, A. Matsumoto, N. Fujii, N. Yamamoto,
Antimicrobial Agents and Chemoth. 1992, 36, 1249-1255; H. Tamamura, M. Kuroda,
M. Masuda, A. Otaka, S. Funakoshi, H. Nakashima, N. Yamamoto, M. Waki, A.
Matsumotu, J.M. in, D. Kohda, S. Tate, F. |nagaki, N. Fujii, Biochim. Biophys.
Acta 1993, 209, 1163; WO 95/10534 A1).
Synthesis of structural analogs and structural studies by r magnetic nce
(NMR) spectroscopy have shown that the ic peptides adopt well defined
pin conformations, due to the constraining effect of one or two disulfide
bridges (H. Tamamura, M. Sugioka, Y. Odagaki, A. Omagari, Y. Kahn, S. Oishi, H.
Nakashima, N. to, S.C. Peiper, N. Hamanaka, A. Otaka, N. Fujii, Bioorg. Med.
Chem. Lett. 2001, 359-362). These results show that the pin structure plays an
important role in CXCR4 antagonizing activity.
Additional structural studies have indicated that the antagonizing activity can also be
influenced by modulating amphiphilic structure and the pharmacophore
(H. Tamamura, A. Omagari, K. Hiramatsu, K. Gotoh, T. Kanamoto, Y. Xu, E. Kodama,
M. ka, T. Hattori, N. Yamamoto, H. Nakashima, A. Otaka, N. Fujii, Bioorg. Med.
Chem. Lett. 2001, 11, 1897-1902; H. Tamamura, A. Omagari, K. tsu, S. Oishi, H.
Habashita, T. Kanamoto, K. Gotoh, N. Yamamoto, H. Nakashima, A. Otaka N. Fujii,
Bioorg. Med. Chem. 2002, 10, 1417-1426; H. Tamamura, K. Hiramatsu, K. Miyamoto,
A. Omagari, S. Oishi, H. Nakashima, N. Yamamoto, Y. Kuroda, T. Nakagawa, A. Otaki,
N. Fujii, Bioorg. Med. Chem. Letters 2002, 12, 923-928).
The compounds cyclo(-Tyr1-HisZ-Xaa3-Cys4-SerS-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cysll-Tyr12-
Xaa13-Xaa14-DProlS-Pr016-), ide bond between Cys4 and Cys“, of the invention are
cyclic B-hairpin peptidomimetics exhibiting high CXCR4 antagonizing activity, being
useful for efficient apheresis collections of mobilized peripheral blood stem cells
and/or using these mobilized cells to regulate tissue repair, and/or having anti-cancer
activity, anti-inflammatory activity and/or anti-HIV activity.
The cyclic B-hairpin conformation is induced by the D-amino acid e Xaa7 and the
D-amino acid residue DProl‘r’. Further stabilization of the hairpin conformation is
achieved by the amino acid residues Cys at positions 4 and 11, which, taken together,
form a disulfide .
Surprisingly we have found that the introduction of the basic amino acid residue
Lys(iPr) at position 14, supported by the optional uction of Orn(iPr) at position 8
of cyclo(—Tyr1-Hisz-Xaa3-Cys4-SerS-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cysll-Tyr12-Xaa13-Xaa14-
DProl‘r’-Pr016-), disulfide bond between Cys4 and Cys“, result in B-hairpin
peptidomimetics which have ble pharmacological properties. These properties,
combined with suitable plasma protein g and appropriate clearance rates form
a pharmacological profile which allows these compounds to be used as active
ingredients in low s for all kind of drug formulations, in particular ed
release drug formulations.
The B-hairpin omimetics of the present invention are compounds of the
general formula
cyclo(-Tyr1-HisZ-Xaa3-Cys4-SerS-Alae-Xaa7-Xaa8-
Arg9-Tyrlo-Cysll-Tyrlz-Xaa13-Xaa14- DProl‘r’-Pr016-) (I),
disulfide bond between Cys4 and Cysll, and ceutically acceptable salts
thereof,
wherein
Xaa3 is Ala, Tyr or Tyr(Me), the latter being (ZS)amino-(4-methoxyphenyl)—
3-propionic acid,
Xaa7 is DTyr, e), i.e. (2R)—2-amino-(4-methoxyphenyl)propionic acid, or DPro,
Xaa8 is Dab, i.e. (ZS)-2,4-diaminobutyric acid, or Orn(iPr), i.e. (ZS)-N°’-isopropyl-
2,5-diaminopentanoic acid,
Xaa13 is Gln or Glu,
Xaa14 is Lys(iPr), i.e. (ZS)-N“’-isopropyl-2,6-diaminohexanoic acid.
In a particular embodiment of the t invention the B-hairpin peptidomimetics
are compounds of the general formula I, in which Xaa13 is Gin, and pharmaceutically
acceptable salts thereof.
In another particular embodiment of the present invention the B-hairpin
peptidomimetics are nds of the general formula I, in which Xaa3 is Tyr; or
Tyr(Me), Xaa7 is DPro, Xaa8 is Orn(iPr) and Xaa13 is Gin, and pharmaceutically
acceptable salts thereof.
In a preferred embodiment of the present invention the compound is
cyclo(-Tyr1-His2-Ala3-Cys4-SerS-Alae-DTyr7-Dab8-Arg9-Tyr10-Cysll-Tyrlz-Gln13-Lys(iPr)14-
DProls-Prole-L disulfide bond between Cys4 and Cysll, and pharmaceutically
acceptable salts thereof.
In another preferred embodiment of the present invention the compound is
cyclo(-Tyr1-HisZ-Tyr3-Cys4-SerS-Alae-DPro7-Orn(iPr)8-Argg-Tyrlo-Cysll-Tyrlz-Gln13-
Lys(iPr)14-DPr015-Pr016-), disulfide bond n Cys4 and Cysll, and pharmaceutically
acceptable salts thereof.
In another preferred embodiment of the present invention the compound is
cyclo(-Tyr1-His2-Tyr(Me)3-Cys4-Ser5-Ala6-DPro7-Orn(iPr)8-ArgQ-Tyrlo-Cysll-Tyrlz-Gln13-
Lys(iPr)14-DPr015-Pr016-), disulfide bond between Cys4 and Cysll, and pharmaceutically
acceptable salts thereof.
In another preferred embodiment of the t invention the compound is
cyclo(-Tyr1-His2-Ala3-Cys4-SerS-Ala6-DTyr(Me)7-Orn(iPr)8-Arg9-Tyr10-Cys11-Tyr12-Gln13-
Lys(iPr)14-DPr015-Pr016-), disulfide bond between Cys4 and Cysll, and ceutically
acceptable salts thereof.
In another preferred embodiment of the present ion the compound is
cyclo(-Tyr1-HisZ-Tyr3-Cys4-SerS-Alae-DTyr7-Orn(iPr)8-ArgQ-Tyrlo-Cysll-Tyrlz-Gln13-
Lys(iPr)14-DPr015-Pr016-), disulfide bond n Cys4 and Cysll, and pharmaceutically
acceptable salts f.
In still r preferred embodiment of the present invention the compound is
cyclo(-Tyr1-HisZ-Tyr(Me)3-Cys4-SerS-Alae-DTyr(Me)7-Orn(iPr)8-Arg9-Tyr10-Cysll-Tyrlz-
Gln13-Lys(iPr)14-DPr015-Pr016-), disulfide bond between Cys4 and Cysll, and
pharmaceutically acceptable salts thereof.
In accordance with the present invention these B-hairpin omimetics can be
ed by a process which comprises
(a) coupling an appropriately functionalized solid support with an appropriately
N-protected derivative of Pro which is in the desired end-product in on
removing the N-protecting group from the product thus obtained;
coupling the product thus obtained with an riately N-protected
derivative of DPro which is in the d end-product in position 15;
removing the ecting group from the product obtained in step (c);
effecting steps substantially corresponding to steps (c) and (d) using
appropriately N-protected derivatives of amino acids which in the desired
end-product are in positions 14 to 1, any functional group(s) which may be
present in said N-protected amino acid derivatives being likewise
appropriately protected;
if desired, forming a disulfide bridge between the hains of the Cys
residues at position 4 and on 11; or alternatively, forming the aforesaid
linkage subsequent to step (i), as described herein below;
ing the product thus obtained from the solid support;
cyclizing the product cleaved from the solid support;
removing any protecting groups present on functional groups of any members
of the chain of amino acid residue; and
if desired, attaching one or several isopropyl groups
if required, removing any protecting groups present on functional groups of
any members ofthe chain of amino acid and
if desired, converting the product thus obtained into a pharmaceutically
acceptable salt or converting a ceutically acceptable, or unacceptable,
salt thus obtained into the corresponding free compound or into a different,
pharmaceutically acceptable, salt.
The B-hairpin peptidomimetics of this invention can be produced, for example, by
following a procedure comprising the synthesis of the linear peptide on resin whereas
the isopropyl group-bearing amino acid residue(s) Orn(iPr) or Lys(iPr) will be
incorporated as amino acid building block(s) being commercially available or
synthesized beforehand; or a procedure comprising the sis of a linear peptide
on resin by applying an orthogonal protecting group gy whereas, for example,
all amino group-bearing side chains of amino acid residues which are not considered
to be modified shall be protected by idee or the like so that amino group-bearing
side chains of amino acid es protected by acid labile protecting groups suitable
to the Fmoc-based solid phase peptide synthesis strategy can be derivatized by
coupling isopropyl groups in solution at a very late stage ofthe synthesis cascade; or
following a procedure comprising a le combination of the procedures described
before.
The proper choice of the functionalized solid-support (i.e. solid support plus linker
molecule) and the site of cyclization play key roles in the synthesis process of the
B-hairpin peptidomimetics of the invention.
The functionalized solid support is conveniently derived from polystyrene inked
with, ably 1-5%, divinylbenzene; polystyrene coated with polyethyleneglycol
spacers (Tentagel®),' and polyacrylamide resins (D. Obrecht, J.-M. Villalgordo, ”Solid-
Supported atorial and Parallel sis of Small-Molecular-Weight
Compound Libraries”, Tetrahedron Organic Chemistry , Vol. 17, Pergamon,
Elsevier Science, 1998).
The solid support is functionalized by means of a linker, i.e. a bifunctional spacer
molecule which contains on one end an anchoring group for attachment to the solid
support and on the other end a selectively cleavable functional group used for the
uent chemical transformations and cleavage procedures. For the purposes of
the present invention two types of linkers are used:
Type 1 linkers are designed to release the amide group under acidic conditions
(H. Rink, Tetrahedron Lett. 1987, 28, 790). Linkers of this kind form amides of
the carboxyl group of the amino acids; examples of resins functionalized by such
linker structures include 4-[(((2,4-dimethoxy-phenyl)Fmoc-aminomethyl)
yacetamido) aminomethyl] PS resin, 4-[(((2,4-dimethoxyphenyl)
Fmoc-aminomethyl)phenoxy-acetamido) aminomethyl] methyl-benzydrylamine PS
resin (Rink amide MBHA PS Resin), and 4-[(((2,4-dimethoxy-phenyl)
Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] benzhydrylamine in
(Rink amide BHA PS resin). Preferably, the support is derived from polystyrene
crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means
of the 4-(((2,4-dimethoxyphenyl) Fmoc-aminomethyl)phenoxyacetamido) linker.
Type 2 linkers are designed to eventually release the carboxyl group under acidic
conditions. Linkers of this kind form acid-labile esters with the carboxyl group of the
amino acids, usually acid-labile benzyl, benzhydryl and trityl esters; examples of such
linker structures include 2-methoxyhydroxymethylphenoxy (SasrinR linker),
4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker), 4-(4-hydroxymethyl-
3-methoxyphenoxy)butyric acid (HMPB linker), trityl and 2-chlorotrityl. Preferably,
the support is derived from polystyrene crosslinked with, most ably 1-5%,
divinyl-benzene and functionalized by means of the 2-chlorotrityl linker.
When d out as el array syntheses the processes of the invention can be
advantageously d out as described herein below but it will be ately
apparent to those skilled in the art how these procedures will have to be modified in
case it is desired to synthesize one single nd of the invention.
A number of reaction s equal to the total number of compounds to be
synthesized by the parallel method are loaded with 25 to 1000 mg, preferably 60 mg,
of the appropriate functionalized solid support, preferably 1 to 3% cross-linked
polystyrene or Tentagel resin.
The t to be used must be capable of swelling the resin and includes, but is not
limited to, dichloromethane (DCM), ylformamide (DMF), N-methylpyrrolidone
(NMP), dioxane, toluene, tetrahydrofuran (THF), l (EtOH), trifluoroethanol
(TFE), isopropylalcohol and the like. Solvent mixtures containing as at least one
component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) are beneficial for
ng high reactivity and solvation of the resin-bound peptide chains (G.B. Fields,
C.G. Fields, J. Am. Chem. 50C. 1991, 113, 4202-4207).
With the development of various s that release the C-terminal carboxylic acid
group under mild acidic conditions, not affecting abile groups protecting
functional groups in the side chain(s), considerable sses have been made in the
synthesis of protected peptide fragments. The 2-methoxyhydroxybenzylalcohol-
derived linker (Sasrin® linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008) is
cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) and is stable to Fmoc
deprotection conditions during the peptide synthesis, Boc/tBu-based additional
ting groups being compatible with this protection scheme. Other linkers which
are suitable for the s of the invention include the super acid labile
4-(2,4-dimethoxyphenyl-hydroxymethyl)—phenoxy linker (Rink linker, H. Rink,
Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of the peptide requires
10% acetic acid in DCM or 0.2% trifluoroacetic acid in DCM; the
4-(4-hydroxymethylmethoxyphenoxy)butyric acid-derived linker (HMPB-linker,
Fl'orsheimer & Riniker, Peptides 1991, 1990 131) which is also cleaved with 1%
TFA/DCM in order to yield a peptide fragment containing all acid labile side-chain
tive groups; and, in addition, the 2-chlorotritylchloride linker (Barlos et al.,
Tetrahedron Lett. 1989, 30, 3943-3946), which allows the peptide detachment using a
mixture ofglacial acetic acid/trifluoroethanol/DCM (1:227) for 30 min.
Suitable protecting groups for amino acids and, respectively, for their residues are,
for example,
- for the amino group (as is present e.g. also in the side-chain of lysine or
ornithine)
Cbz benzyloxycarbonyl
Boc utyloxyca rbonyl
Fmoc 9-fluorenylmethoxycarbonyl
Alloc allyloxycarbonyl
Teoc hylsilylethoxycarbonyl
ch trichloroethoxycarbonyl
Nps o-nitrophenylsulfonyl;
Trt triphenymethyl or trityl
idee (4,4-dimethyl-2,6-dioxocyclohexylidene)
methylbutyl
- for the carboxyl group (as is present e.g. also in the side-chain ofglutamic
acid) by conversion into esters with the alcohol components
tBu tert-butyl
Bn benzyl
Me methyl
Ph phenyl
Pac phenacyl
allyl
Tse trimethylsilylethyl
Tce trichloroethyl;
idee (4,4-dimethyl-2,6-dioxocyclohexylidene)methylbutyl
- for the guanidino group (as is present e.g. in the side-chain of ne)
Pmc 2,2,5,7,8—pentamethylchromansulfonyl
Ts tosyl (i. e. p-toluenesulfonyl)
Cbz benzyloxycarbonyl
be pentamethyldihydrobenzofuransulfonyl
- for the y group (as is present e.g. in the side-chain of serine)
tBu tert-butyl
Bn benzyl
Trt trityl
Alloc allyloxycarbonyl
- and for the mercapto group (as is present e.g. in the side-chain of cysteine)
Acm acetamidomethyl
tBu tert-butyl
Bn benzyl
Trt trityl
Mtr 4-methoxytrityl.
The 9-fluorenylmethoxycarbonyl (Fmoc) -protected amino acid derivatives are
preferably used as the building blocks for the construction of the B-hairpin loop
mimetics of the invention. For the deprotection, i. e. cleaving off of the Fmoc group,
% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.
The linkage of pyl groups to amino group-bearing side chains of
9-fluorenylmethoxycarbonyl (Fmoc) -protected amino acid derivatives to form
pylated amino bearing side chains of (Fmoc) -protected amino acid
derivatives is known in the art. The procedure for introducing an isopropyl group can
be accomplished e.g. by reductive alkylation e.g. treatment ofthe amino group of the
amino bearing side chain of an amino acid building block like e.g. Orn with
acetone in the presence of a suitable reducing agent like e.g. sodium
triacetoxyborohydride. Protecting groups like e.g Boc suitable for ispropylated amino
group-bearing side chains of (Fmoc) -protected amino acid derivatives can be
introduced by subsequent reaction with di-tert-butyl dicarbonate in the presence of a
base such as sodium bicarbonate.
The quantity of the reactant, i. e. of the amino acid derivative, is usually 1 to 20
equivalents based on the milliequivalents per gram ) loading of the
functionalized solid support (typically 0.1 to 2.85 meq/g for polystyrene resins)
originally weighed into the reaction tube. Additional equivalents of reactants can be
used, if required, to drive the on to completion in a reasonable time. The
preferred workstations (without, however, being limited thereto) are Labsource's
Combi-chem station, Protein logies’ ny and MultiSyn Tech's-Syro
synthesizer, the latter additionally ed with a transfer unit and a reservoir box
during the process of detachment of the fully ted linear peptide from the solid
support. All synthesizers are able to provide a controlled environment, for example,
reactions can be accomplished at temperatures ent from room temperature as
well as under inert gas atmosphere, if desired.
Amide bond formation requires the activation of the oc-carboxyl group for the
acylation step. When this activation is being carried out by means of the commonly
used carbodiimides such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am.
Chem. Soc. 1955, 77, 068) or ropylcarbodiimide (DIC, Sarantakis et al
Biochem. Biophys. Res. . 1976, 73, 336-342), the ing dicyclohexylurea
and, respectively, diisopropylurea is insoluble and, respectively, soluble in the
solvents generally used. In a variation of the carbodiimide method
1-hydroxybenzotriazole (HOBt, K'onig & Geiger, Chem. Ber. 1970, 103, 788-798) is
included as an additive to the coupling mixture. HOBt prevents dehydration,
suppresses racemization of the activated amino acids and acts as a catalyst to
improve the sh coupling reactions. Certain phosphonium reagents have been
used as direct coupling reagents, such as benzotriazol-l-yl-oxy-tris-(dimethyl-
-phosphonium hexafluorophosphate (BOP, Castro et a|., Tetrahedron Lett.
1975, 14, 1219-1222; Synthesis 1976, 751-752), or benzotriazol-l-yl-oxy-tris-
pyrrolidino-phosphonium hexaflurophoshate P, Coste et a|., Tetrahedron Lett.
1990, 31, 205-208), or 2-(1H-benzotriazolyl-)1,1,3,3-tetramethyluronium tetra-
fluoroborate (TBTU), or hexafluorophosphate (HBTU, Knorr et a|., edron Lett.
1989, 30, 1927-1930); these phosphonium reagents are also le for in situ
formation of HOBt esters with the protected amino acid derivatives. More recently
diphenoxyphosphoryl azide (DPPA) or O-(7-aza-benzotriazolyl)-N,N,N’,N’-tetra-
methyluronium tetrafluoroborate (TATU) or O-(7-aza-benzotriazol-l-yl)-
N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU)/7-azahydroxy benzo-
triazole (HOAt, Carpino et a|., Tetrahedron Lett. 1994, 35, 2279-2281) or
-(6-Chloro-1H-benzotriazol-l-yl-)—N,N,N’,N’-1,1,3,3-tetramethyl-uronium tetrafluoroborate
(TCTU), or hexafluorophosphate (HCTU, Marder, Shivo and Albericio: HCTU
and TCTU: New Coupling Reagents: Development and Industrial Applications, Poster
Presentation, Gordon Conference February 2002) have also been used as coupling
reagents as well as 3-bis(tetramethylene)chlorouronium hexafluoro-phosphate
(PyClU, especially for coupling N-methylated amino acids, J. Coste, E. Frérot, P. Jouin,
B. Castro, edron Lett. 1991, 32, 1967) or pentafluorophenyl diphenyl-
phosphinate (S. Chen, J. Xu, Tetrahedron Lett. 1991, 32, 6711).
Due to the fact that near-quantitative coupling reactions are essential, it is desirable
to have experimental ce for tion of the reactions. The ninhydrin test
(Kaiser et a|., Anal. Biochemistry 1970, 34, 595), where a positive colorimetric
se to an aliquot of resin-bound peptide indicates qualitatively the presence of
the primary amine, can easily and quickly be performed after each coupling step.
Fmoc chemistry allows the spectrophotometric detection of the Fmoc chromophore
when it is released with the base (Meienhofer et a|., Int. J. Peptide Protein Res. 1979,
13, 35-42).
The resin-bound intermediate within each reaction vessel is washed free of excess of
retained reagents, of solvents, and of by-products by repetitive exposure to pure
so|vent(s) by one of the two following methods:
1) The reaction vessels are filled with solvent (preferably 5 mL), ed for 5 to
300 minutes, preferably 15 minutes, and drained to expel the solvent;
2) The reaction vessels are filled with solvent (preferably 5 mL) and drained into a
receiving vessel such as a test tube or vial.
Both of the above washing procedures are repeated up to about 50 times rably
about 10 times), monitoring the efficiency of reagent, solvent, and by-product
removal by methods such as TLC, GC, or inspection ofthe washings.
The above bed procedure of reacting the resin-bound compound with reagents
within the reaction tubes followed by removal of excess reagents, by-products, and
solvents is ed with each successive transformation until the final bound
fully protected linear peptide has been obtained.
Before this fully protected linear e is detached from the solid support, a
disulfide bridge n Cys4 and Cys11 can be formed.
For the formation of a disulfide bridge preferably a solution of 10 equivalents of
iodine solution is applied in DMF or in a mixture of CHZCIZ/MeOH for 1.5 h which is
repeated for another 3h with a fresh iodine solution after filtering of the iodine
on, or in a mixture of DMSO and acetic acid solution, buffered with 5% NaHC03
to pH 5-6 for 4 h, or in water after adjusting to pH 8 with ammonium hydroxide
solution by ng for 24 h, or in a solution of NMP and tri-n-butylphosphine
(preferably 50 eq.).
Alternatively, the formation of the disulfide bridge between Cys4 and Cys11 can be
carried out subsequent to the work-up method 2), as described herein below, by
stirring the crude fully deprotected and cyclized peptide for 24h in water containing
DMSO up to 15% by volume, buffered with 5% NaHC03 to pH 5-6, or buffered with
ammonium acetate to pH 7-8, or adjusted with ammonium hydroxide to pH 8.
ing ation to dryness cyclo(-Tyr1-HisZ-Xaas-Cys4-SerS-Alae-Xaa7-Xaa8-
Arg9-Tyrlo-Cysll-Tyrlz-Xaa13-Xaa14-DPr015-Pr016-), disulfide bond between Cys4 and
Cys11 is obtained as end-product.
Detachment of the fully protected linear peptide from the solid support is achieved
by exposing the loaded resin with a solution of the reagent used for ge
(preferably 3 to 5 mL). Temperature control, agitation, and reaction monitoring are
implemented as described above. Via a transfer-unit the reaction vessels are
connected with a reservoir box ning reservoir tubes to efficiently collect the
cleaved product solutions. The resins remaining in the reaction vessels are then
washed 2 to 5 times as above with 3 to 5 mL of an appropriate t to extract
(wash out) as much of the detached products as possible. The t solutions thus
ed are combined, taking care to avoid cross-mixing. The individual
solutions/extracts are then manipulated as needed to isolate the final compounds.
Typical manipulations include, but are not limited to, evaporation, concentration,
liquid/liquid extraction, acidification, basification, neutralization or additional
ons in solution.
The solutions containing fully protected linear peptide derivatives which have been
cleaved off from the solid support and lized with a base, are evaporated.
Cyclization is then effected in solution using solvents such as DCM, DMF, dioxane, THF
and the like. Various coupling reagents which were ned earlier can be used for
the ation. The duration of the cyclization is about 6-48 h, preferably about 16 h.
The progress of the reaction is followed, e. g. by RP-HPLC se Phase High
Performance Liquid Chromatography). Then the solvent is removed by evaporation,
the fully protected cyclic peptide derivative is dissolved in a solvent which is not
miscible with water, such as DCM, and the solution is extracted with water or a
mixture of water-miscible solvents, in order to remove any excess of the coupling
reagent.
Finally, the fully protected peptide tive is treated with 95% TFA, 2.5% H20, 2.5%
TIS or r combination of scavengers for effecting the cleavage of protecting
groups. The ge reaction time is commonly 30 minutes to 12h, preferably about
2.5 h.
Alternatively, the detachment and complete deprotection of the fully protected
peptide from the solid support can be achieved manually in glass vessels.
After full deprotection, for example, the following methods can be used for further
work-up:
1) The volatiles are evaporated to dryness and the crude peptide is dissolved in
20% AcOH in water and extracted with isopropyl ether or other solvents which are
suitable therefor. The aqueous layer is collected and evaporated to dryness, and the
fully deprotected e, cyclo(-Tyr1-HisZ-Xaas-Cys4-SerS-Alae-Xaa7-Xaa8-
Arg9-Tyrlo-Cysll-Tyrlz-Xaa13-Xaa14-DPr015-Pr016-), disulfide bond between Cys4 and
Cysll, is ed as final t;
2) The deprotection e is concentrated under vacuum. Following
precipitation of the fully deprotected peptide in diethylether at preferably 0 °C the
solid is washed up to about 10 times, preferably 3 times, dried, and the the fully
deprotected peptide, cyclo(-Tyr1-HisZ-Xaa3-Cys4-SerS-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-
TyrlZ-Xaa13-Xaa14-DProls-Pr016-), disulfide bond between Cys4 and Cys11,is obtained as
final product, if a disulfide bond between Cys4 and Cys11 has been formed on solid
support as described herein above.
If the above mentioned orthogonal protecting group strategy for introducing one or
more pyl groups in solution has been followed, then all amino groups of side
chains of amino acid residues are still protected by non-acid labile ting groups
s amino groups of amino acid residues formerly protected by acid labile
protecting groups have been liberated at this stage of the synthesis cascade. Thus, it
is possible, if desired, to couple an isopropyl group. Preferably, idee or the like are
acid stable protecting groups for amino group bearing side chains which are kept
fied during the coupling of isopropyl groups to liberated amino groups. This
coupling can be accomplished by applying e.g. a reductive alkylation using acetone in
the presence ofa suitable reducing agent like e.g. sodium cyano borhydride. Thus, for
example, the peptide is dissolved in MeOH (4.4 mM) containing acetic acid (0.2 M).
After adding an excess of acetone (780 eq) the reaction mixture is completed with a
solution of sodium cyano borhydride in MeOH (0.6 M; 1.3 eq per isopropyl group
desired to be introduced) and vigorously shaken at room temperature. Following
tion of the conversion monitored by LC-MS, water is added and the solvents
are evaporated. The residual solid containing the peptide is dissolved in DMF (0.01 M)
and a solution of 5% hydrazine in DMF is used to finally remove the idee-protecting
groups.
As mentioned earlier, it is fter possible, if desired, to convert the fully
deprotected cyclic product thus obtained into a pharmaceutically able salt or
to t a pharmaceutically acceptable, or unacceptable, salt thus obtained into
the corresponding free compound or into a different, pharmaceutically acceptable,
salt. Any of these operations can be carried out by methods well known in the art.
The B-hairpin peptidomimetics of the invention can be used in a wide range of
applications in order to prevent HIV infections in healthy individuals and slow or halt
viral progression in infected patients, or where cancer is mediated or resulting from
the CXCR4 receptor activity, or where immunological diseases are mediated or
resulting from CXCR4 or activity; or these B-hairpin omimetics can be
used to treat immunosuppression, or they can be used during apheresis collections of
eral blood stem cells and/or as agents to induce mobilization of stem cells to
te tissue repair.
The B-hairpin peptidomimetics of the ion may be administered per se or may
be applied as an appropriate formulation together with carriers, diluents or excipients
well known in the art.
When used to treat or prevent HIV infections or cancer such as breast cancer, brain
cancer, prostate cancer, heptatocellular carcinoma, colorectal cancer, lung cancer,
kidney cancer, neuroblastoma, ovarian cancer, endometrial cancer, germ cell tumor,
eye cancer, multiple myeloma, pancreatic cancer, gastric ,
rhabdomyo-sarcoma, melanoma, c lyphomphocytic leukemia, acute
myelogenous leukemia, acute lymphoblastic leukemia, multiple myeloma and
Non-Hodgkin’s lymphoma; metastasis, angiogenesis, and haematopoetic tissues; or
inflammatory disorders such as asthma, allergic rhinitis, hypersensitivity lung
diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type
hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary is, ILD
associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing
sponylitis, ic sclerosis, Sjogren‘s syndrome, systemic anaphylaxis or
hypersensitivity ses, drug allergies, rheumatoid tis, psoriatic arthritis,
multiple sclerosis, Alzheimer’s disease, Parkinson’s e, atherosclerosis,
myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune
throiditis, graft rejection, including allograft rejection or graft-versus-host disease,
inflammatory bowel es and inflammatory dermatoses; or to treat eye diseases
like glaucoma, diabethic retinopathy and age related macular degeneration; or to
treat focal ischemic stroke, global cerebral ischemia, myocardial infarction, hind limb
ischemia or peripheral ischemia; or to treat injury of the liver, kidney or lung; or to
treat immunosuppression, including immunosuppression induced by chemotherapy,
ion therapy or graft/transplantation rejection, the B-hairpin peptidomimetics of
the invention can be administered singly, as mixtures of several B-hairpin
peptidomimetics, in combination with other anti-HIV agents, or antimicrobial agents
or anti-cancer agents or anti-inflammatory agents, or in combination with other
pharmaceutically active agents. The B-hairpin peptidomimetics of the invention can
be administered per se or as pharmaceutical compositions.
Pharmaceutical itions comprising B-hairpin peptidomimetics of the invention
may be manufactured by means of conventional mixing, dissolving, ating,
coated tablet-making, levigating, emulsifying, ulating, entrapping or
lyophilizing processes. Pharmaceutical compositions may be formulated in
conventional manner using one or more physiologically acceptable carriers, diluents,
excipients or iaries which facilitate processing of the active B-hairpin
peptidomimetics into preparations which can be used pharmaceutically. Proper
formulation depends upon the method of administration chosen.
For topical administration the B-hairpin peptidomimetics of the invention may be
formulated as ons, gels, ointments, creams, suspensions, powders, etc. as are
well-known in the art.
Systemic formulations include those designed for administration by ion, e.g.
subcutaneous, intravenous, uscular, intrathecal or intraperitoneal injection, as
well as those designed for transdermal, transmucosal, oral or pulmonary
administration.
For injections, the B-hairpin peptidomimetics of the invention may be ated in
adequate solutions, preferably in physiologically compatible buffers such as Hink’s
on, Ringer’s solution, or physiological saline buffer. The ons may contain
formulatory agents such as suspending, stabilizing and/or sing agents.
Alternatively, the B-hairpin peptidomimetics of the invention may be in powder form
for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
WO 68336
For ucosal administration, penetrants appropriate to the barrier to be
permeated are used in the ation as known in the art.
For oral administration, the compounds can be readily ated by combining the
active B-hairpin peptidomimetics of the invention with pharmaceutically acceptable
carriers well known in the art. Such carriers enable the B-hairpin peptidomimetics of
the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups,
es, suspensions, powders etc., for oral ingestion by a patient to be treated. For
oral formulations such as, for e, powders, capsules and tablets, suitable
excipients e fillers such as sugars, such as e, sucrose, mannitol and
sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato
starch, n, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating
agents; and binding agents. If desired, desintegrating agents may be added, such as
cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as
sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated
using rd techniques.
For oral liquid preparations such as, for example, suspensions, elixirs and solutions,
suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In
addition, flavoring agents, preservatives, coloring agents and the like may be added.
For buccal administration, the composition may take the form of tablets, lozenges,
etc. formulated as usual.
The nds may also be formulated in rectal or vaginal compositions such as
suppositories together with appropriate suppository bases such as cocoa butter or
other glycerides.
In addition to the formulations described above, the B-hairpin peptidomimetics of the
invention may also be ated as depot ations. Such long acting
formulations may be administered by implantation (e.g. subcutaneously or
intramuscularly) or by intramuscular injection. For the manufacture of such depot
preparations the pin peptidomimetics of the invention may be formulated with
le polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil)
or ion exchange resins, or as sparingly soluble salts.
In addition, other ceutical delivery s may be employed such as
liposomes and emulsions well known in the art. Certain organic ts such as
ylsulfoxide may also be employed. Additionally, the B-hairpin peptidomimetics
of the invention may be delivered using a sustained-release system, such as
semipermeable matrices of solid polymers containing the therapeutic agent (e.g. for
coated stents). Various sustained-release materials have been established and are
well known by those skilled in the art. Sustained-release capsules may, depending on
their chemical nature, release the compounds for a few weeks up to over 100 days.
Depending on the chemical nature and the biological stability of the eutic
agent, additional strategies for protein stabilization may be employed.
As the B-hairpin peptidomimetics of the invention contain charged residues, they may
be included in any of the above bed ations as such or as
ceutically acceptable salts. Pharmaceutically acceptable salts tend to be more
soluble in aqueous and other protic solvents than are the corresponding free forms.
Particluarly suitable pharmaceutically acceptable salts include salts with carboxylic,
phosphonic, sulfonic and sulfamic acids, e.g. acetic acid, propionic acid, octanoic acid,
decanoic acid, dodecanoic acid, ic acid, lactic acid, fumaric acid, succinic acid,
adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid,
amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic
acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic
acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid,
ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-
naphthalenedisulfonic acid, 2-, 3- or 4-methyl-benzenesulfonic acid, sulfuric
acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-,
N-ethyl- or N-propyl-sulfamic acid, and other organic protonic acids, such as ascorbic
acid. Suitable inorganic acids are for example hydrohalic acids, such as hydrochloric
acid, sulfuric acid and phosphoric acid.
The B-hairpin peptidomimetics of the invention, or compositions thereof, will
generally be used in an amount effective to achieve the intended purpose. It is to be
tood that the amount used will depend on a particular application.
For topical administration to treat or prevent HIV infections a therapeutically
effective dose can be determined using, for example, the in vitro assays provided in
the examples. The treatment may be applied while the HIV infection is e, or even
when it is not visible. An ordinary skilled expert will be able to determine
therapeutically effective amounts to treat topical HIV infections without undue
mentation.
For systemic administration, a therapeutically effective dose can be estimated initially
from in vitro . For example, a dose can be formulated in animal models to
e a circulating B-hairpin omimetic concentration range that includes the
IC50 as determined in the cell culture. Such information can be used to more
accurately determine useful doses in humans.
l dosages can also be determined from in vivo data, e.g. animal models, using
techniques that are well known in the art. One having ordinary skill in the art could
readily optimize administration to humans based on animal data.
Dosage amounts for applications as anti-HIV agents may be adjusted individually to
provide plasma levels of the B-hairpin peptidomimetics of the ion which are
sufficient to maintain the therapeutic effect. Therapeutically ive serum levels
may be achieved by stering multiple doses each day.
In cases of local administration or selective uptake, the effective local concentration
of the B-hairpin peptidomimetics of the invention may not be related to plasma
concentration. One having the ordinary skill in the art will be able to optimize
therapeutically effective local dosages without undue mentation.
The amount of B-hairpin peptidomimetics administered will, of course, be dependent
on the subject being treated, on the subject’s weight, the severity of the affliction,
the manner of administration and the judgement ofthe prescribing physician.
The anti-HIV therapy may be repeated intermittently while infections are detectable
or even when they are not detectable. The y may be provided alone or in
combination with other drugs, such as for example other anti-HIV agents or anti-
cancer agents, or other antimicrobial agents.
Normally, a therapeutically effective dose ofthe B-hairpin peptidomimetics described
herein will provide therapeutic benefit without causing substantial toxicity.
Toxicity of the pin peptidomimetics of the invention can be determined by
standard pharmaceutical ures in cell es or experimental animals, e.g., by
determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose
lethal to 100% of the population). The dose ratio n toxic and therapeutic
effect is the therapeutic index. Compounds which exhibit high therapeutic indices are
red. The data obtained from these cell culture assays and animal studies can be
used in formulating a dosage range that is not toxic for use in humans. The dosage of
the B-hairpin peptidomimetics of the invention lies preferably within a range of
circulating concentrations that include the effective dose with little or no toxicity.
The dosage may vary within the range depending upon the dosage form employed
and the route of administration utilized. The exact formulation, route of
administration and dose can be chosen by the dual physician in view of the
t’s condition (see, e.g. Fingl et al. 1975, In: The cological Basis of
Therapeutics, Ch.1, p.1).
WO 68336
The t invention may also include compounds, which are identical to the
compounds of the general formula cyclo(-Tyr1-HisZ-Xaas-Cys4-SerS-Alae-Xaa7-Xaa8-
Arg9-Tyrlo-Cysll-Tyrlz-Xaa13-Xaa14-DPr015-Pr016-), disulfide bond between Cys4 and
Cysll, except that one or more atoms are ed by an atom having an atomic mass
number or mass different from the atomic mass number or mass usually found in
nature, e.g. compounds enriched in 2H (D), 3H, 11C, 14C, 129| etc. These isotopic analogs
and their pharmaceutical salts and formulations are considered useful agents in the
therapy and/or stic, for example, but not limited to, where a fine-tuning of in
vivo half-life time could lead to an optimized dosage regimen.
The following Examples illustrate the present invention but are not to be construed as
limiting its scope in any way.
Examples
1. Peptide Synthesis
Coupling of the first protected amino acid residue to the resin
1 g (1.4 mMol) 2-chlorotritylchloride resin (1.4 mMol/g; 100 — 200 mesh,
copoly(styrene-1% DVB) polymer matrix; Barlos et al. Tetrahedron Lett. 1989, 30,
3943-3946) was filled into a dried flask. The resin was suspended in CHZCIZ (5 mL) and
d to swell at room temperature under constant shaking for 30 min. A solution
of 0.98 mMol (0.7 eq) of the first ly protected amino acid residue (see below) in
CHZCIZ (5 mL) mixed with 960 pl (4 eq) of diisopropylethylamine (DIEA) was added.
After shaking the reaction mixture for 4 h at 25 °C, the resin was ed off and
washed successively with CHZCIZ (1x), DMF (1x) and CHZCIZ (1x). A solution of
CHZCIZ/MeOH/DIEA (17/2/1, 10 mL) was added to the resin and the suspension was
shaken for 30 min. After filtration the resin was washed in the following order with
CH2C|2(1x), DMF (1x), CH2C|2(1x), MeOH (1x), CHZCIZ (1x), MeOH (1x), CHZCIZ (2x), EtZO
(2x) and dried under vacuum for 6 hours.
Loading was lly 0.6-0.7 mMol/g.
The following preloaded resins was prepared:
Fmoc-Pro-Z-chlorotrityl resin.
The synthesis was carried out employing a Syro-peptide synthesizer (MultiSynTech)
using 24-96 on vessels. In each vessel 0.04 mMol of the above resin was placed
and the resin was swollen in CHZCIZ and DMF for 15 min, respectively. The following
reaction cycles were programmed and carried out:
Step Reagent Time
1 DMF, wash 2x1 min
2 20% piperidine/DMF 1x5 min, 1x15 min
3 DMF, wash 5x1 min
4 5 eq Fmoc amino acid/DMF
+5 eq Py-BOP/DMF, 10 eq MF 1x60 min
DMF, wash 3x1 min
Step 4 was repeated once.
Unless indicated otherwise, the final coupling of an amino acid was followed by Fmoc
deprotection by applying steps 1-3 ofthe above described reaction cycle.
Amino acid building block syntheses
sis of Fmoc-Orn(iPr,Boc)-OH
The synthesis of (2S)—N°‘-fluorenylmethoxylcarbonyl-N‘”,Nw-tert-butyloxycarbonyl-
isopropyl-2,5-diaminopentanoic acid was lished by suspending 15.2 g Fmoc-
Orn-OH*HC| in 150 mLTHF (0.26 M) followed by adding 375 mL acetone (132 eq) and
.6 g sodium triacetoxyborohydride (2.5 eq). The reaction mixture was stirred for 2 h
and subsequent to completion of the on (monitored by LC-MS) 120 mL of sat.
Na2C03-solution and 10.2 g Boc20 (1.2 eq) were added. After stirring overnight sat.
Na2C03-solution and BocZO were added again twice in ns according to the
remaining starting material. Following completion of the Boc-introduction hexane
was added twice, separated, and the aqueous layer was acidified with 5 N HClaq (pH =
1) and extracted thrice with ethyl acetate thereafter. Finally, the combined organic
layers were dried with Na2S04 and evaporated to obtain the product as white foam.
The amino acid building block Fmoc-Lys(iPr,Boc)-OH can be synthesized accordingly or
is commercially available.
The amino acid building blocks Fmoc-Tyr(Me)-OH and Fmoc-DTyr(Me)-OH are
commercially available as well.
Cyclization and work up of backbone cyclized peptides
Cleavage of the fully protected peptide fragment
After completion ofthe synthesis, the resin (0.04 mMol) was suspended in 1 mL (0.13
mMol, 3.4 eq) of 1% TFA in CHZCIZ (v/v) for 3 minutes, filtered, and the filtrate was
neutralized with 1 mL (0.58 mMol, 14.6 eq) of 10% DIEA in CHZCIZ (v/v). This
procedure was repeated three times to ensure completion of the cleavage. The
filtrate was evaporated to dryness and a sample ofthe product was fully deprotected
by using a ge mixture ning 95% oroacetic acid (TFA), 2.5% water and
2.5% triisopropylsilane (TIS) to be ed by reverse phase-HPLC (C18 column) and
ESI-MS to monitor the efficiency of the linear peptide synthesis.
Cyclization of the linear peptide
The fully protected linear peptide (0.04 mMol) was dissolved in DMF (4 uMol/mL).
Then 30.4 mg (0.08 mMol, 2 eq) of HATU, 10.9 mg (0.08 mMol, 2 eq) of HOAt and 28
ul (0.16 mMol, 4 eq) DIEA were added, and the mixture was ed at 25 °C for
16 hours and uently concentrated under high vacuum. The residue was
partitioned between CHZCIZ and HZO/CH3CN (90/10: v/v). The CHZCIZ phase was
evaporated to yield the fully protected cyclic peptide.
Full deprotection of the cyclic peptide
The cyclic peptide obtained was dissolved in 3 mL of the cleavage mixture containing
82.5% trifluoroacetic acid (TFA), 5% water, 5% thioanisole, 5% phenol and 2.5%
ethanedithiole (EDT). The mixture was allowed to stand at 25 °C for 2.5 hours and
thereafter concentrated under vacuum. After itation of the cyclic fully
deprotected e in diethylether (EtZO) at 0 °C the solid was washed twice with
EtZO and dried.
Formation of disulfide ,B-strand linkage and purification
After full deprotection, the crude peptide was dissolved in 0.1 M ammonium acetate
buffer (1 mg/ 1 mL, pH = 7-8). DMSO (up to 5% by volume) was added and the
solution was shaken overnight. Following evaporation the residue was purified by
ative e phase HPLC.
After lyophilisation the products were obtained as white powders and analysed by
the following analytical method: Analytical HPLC retention times (RT, in minutes)
were determined using a Ascentis Express C18 column, 50 x 3.0 mm, (cod. 53811-U-
Supelco) with the following solvents A (H20 + 0.1% TFA) and B (CH3CN + 0.1% TFA)
and the gradient: 0005 min: 97% A, 3% B; 3.4 min: 33% A 67% B; 3.41-3.65 min: 3%
A, 97% B; 3.66-3.7 min: 97% A, 3% B. Flow rate = 1.3 mL/min; UV_Vis = 220 nm.
Example 1:
Starting resin was Fmoc-Pro-Ochlorotrityl resin, which was prepared as described
above. To that resin DPro, finally at position 15, was grafted. The linear peptide was
sized on solid support according to the procedure described above in the
ing sequence: Resin-Prole-DProls-LysfiPr)14-Gln13-Tyr12-Cysll-Tyrlo-Argg-
Orn(iPr)8-DPro7-Ala6-SerS-Cys4-Tyr3-His2-Tyr1. Following a final Fmoc deprotection as
described above, the peptide was cleaved from the resin, cyclized, deprotected and,
after formation of the ide B-strand linkage as described above, purified as
ted above.
The HPLC-retention time (minutes) was ined using the analytical method as
described above (UV-purity [after preparative HPLC]: 95%; RT: 1.56; [M+3H]/3 =
685.7).
Example 2: Starting resin was ro-Ochlorotrityl resin, which was prepared as
described above. To that resin DPro, finally at position 15, was grafted. The linear
peptide was sized on solid support according to the procedure described above
in the following sequence: Resin-Prole-DProls-LysfiPr)14-Gln13-Tyr12-Cysll-Tyrlo-Argg-
r)8-DPro7-Ala6-Ser5-Cys4-Tyr(Me)3-His2-Tyr1. Following a final Fmoc deprotection
as described above, the peptide was cleaved from the resin, cyclized, deprotected
and, after formation of the disulfide B-strand linkage as described above, purified as
indicated above.
The HPLC-retention time es) was determined using the analytical method as
described above rity [after preparative HPLC]: 95%; RT: 1.7; /3 =
690.4).
Example 3: Starting resin was Fmoc-Pro-Ochlorotrityl resin, which was prepared as
described above. To that resin DPro, finally at position 15, was grafted. The linear
peptide was synthesized on solid support according to the procedure bed above
in the following sequence: Resin-ProlG-DProls-LysfiPr)14-Gln13-Tyr12-Cys11-Tyr10-
Arg9-Dab8-DTyr7-Ala6-SerS-Cys4-Ala3-His2-Tyr1. Following a final Fmoc deprotection as
described above, the peptide was cleaved from the resin, cyclized, deprotected and,
after formation of the disulfide B-strand linkage as described above, purified as
indicated above.
The HPLC-retention time (minutes) was determined using the analytical method as
described above (UV-purity [after preparative HPLC]: 95%; RT: 1.57; [M+3H]/3 =
658.3).
WO 68336
Example 4: ng resin was Fmoc-Pro-Ochlorotrityl resin, which was prepared as
described above. To that resin DPro, finally at position 15, was grafted. The linear
e was synthesized on solid support according to the procedure described above
in the following sequence: Resin-ProlG-DProls-LysfiPr)14-Gln13-Tyr12-Cys11-Tyr10-
Arg9-Orn(iPr)8-DTyr(Me)7-Ala6-Ser5-Cys4-Ala3-HisZ-Tyrl. Following a final Fmoc
deprotection as described above, the peptide was cleaved from the resin, cyclized,
deprotected and, after formation of the disulfide B-strand linkage as described above,
purified as indicated above.
The HPLC-retention time (minutes) was determined using the analytical method as
bed above (UV-purity [after preparative HPLC]: 95%; RT: 1.70; /3 =
681.7).
Example 5: Starting resin was Fmoc-Pro-Ochlorotrityl resin, which was prepared as
described above. To that resin DPro, y at position 15, was grafted. The linear
peptide was synthesized on solid support according to the procedure described above
in the following sequence: Resin-ProlG-DProls-LysUPr)14-Gln13-Tyr12-Cys11-Tyr10-
Arg9-Orn(iPr)8-DTyr7-Ala6-SerS-Cys4-Tyr3-His2-Tyr1. Following a final Fmoc deprotection
as described above, the peptide was cleaved from the resin, cyclized, deprotected
and, after formation of the disulfide B-strand e as described above, purified as
indicated above.
The HPLC-retention time (minutes) was determined using the analytical method as
bed above (UV-purity [after preparative HPLC]: 95%; RT: 1.60; /3 =
707.4).
Example 6: Starting resin was Fmoc-Pro-Ochlorotrityl resin, which was prepared as
described above. To that resin DPro, finally at position 15, was grafted. The linear
peptide was synthesized on solid support according to the procedure described above
in the following sequence: Resin-ProlG-DProls-LysfiPr)14-Gln13-Tyr12-Cys11-Tyr10-
ArgQ-Orn(iPr)8-DTyr(Me)7-Ala6-Ser5-Cys4-Tyr(Me)3-His2-Tyr1. Following a final Fmoc
ection as described above, the peptide was cleaved from the resin, cyclized,
deprotected and, after formation of the disulfide B-strand linkage as described above,
purified as indicated above.
The HPLC-retention time (minutes) was determined using the ical method as
described above (UV-purity [after preparative HPLC]: 95%; RT: 1.83; [M+3H]/3 =
717.0).
2. ical methods
2.1. Preparation of the peptides
Lyophilized es were weighed on a Microbalance (Mettler MT5) and ved in
DMSO to a final concentration of 10 mM. Stock solutions were kept at +4 °C, light
protected. The biological assays were carried out under assay conditions having less
than 1% DMSO unlike indicated otherwise.
2.2. Cell culture
Namalwa cells (CXCR4 natively expressing herent cells, ATCC CRL-1432) were
cultured in RPM|1640 plus 10% FBS, and rept. HELA cells were maintained in
RPM|1640 plus 10% FBS, pen/strept and 2 mM L-glutamine. Cos-7 cells were grown in
DMEM medium with 4500 mg/mL glucose supplemented with 10% FCS, pen/strept
and 2 mM amine. All cell lines were grown at 37 °C at 5% C02. Cell media, media
supplements, PBS-buffer, HEPES, antibiotic/antimycotic, pen/strept, non essential
amino acid, amine, B-mercaptoethanol and sera were purchased from Gibco
(Pailsey, UK). All fine chemicals were supplied by Merck (Darmstadt, Germany).
2.3. Chemotactic Assay (Cell migration assay)
The Chemotactic response of Namalwa cells (ATCC CRL-1432) to a gradient of stromal
cell-derived factor lot (SDF-l) was measured using a modified Boyden chamber
chemotaxis system (ChemoTx; Neuroprobe). In this system, the upper chamber of
each well is separated from the lower chamber containing the chemoattractant SDF-l
by a polycarbonate membrane (5pm pore size). A circular area of that membrane in
the region that covers each lower well is enclosed by a hydrophobic mask to retain
2012/060763
the cell suspension within this area. The system was prepared by loading the bottom
wells with aliquots of 30 (LL of chemotaxis medium (RPMI 1640 without Phenol red +
0.5% BSA) comprising either riate serial dilutions of peptides or no peptide at
all in ation with SDF-1 (0.9 nM) or without the ttractant. The
membrane was placed over the bottom wells, and aliquots of 50 (LL of a suspension of
Namalwa cells (3.6 x 106 cells/mL) in chemotaxis medium, premixed with chemotaxis
medium comprising either appropriate serial ons of peptides or no peptide at all,
was delivered onto each of the hydrophobically limited regions of the upper surface
ofthe membrane. The cells were allowed to migrate into the bottom chamber for 5 h
at 37 °C in 5% C02. After this period, the membrane was removed and its topside was
carefully wiped and washed with PBS to eliminate non-migrated cells. Migrated cells
were transferred using a ”funnel” r to a receiving 96-well plate and the cell
number was determined by using the CyQuantTM NF cell proliferation assay
(Invitrogen) based on the measurement of cellular DNA content via fluorescent dye
binding. Following the manufacturer’s directions, 50 (LL of tTM dye
reagent/HBSS buffer (1/500 [v/v]) were added to each well of the above mentioned
receiving 96-well plate. After incubation for 0.5 h at room temperature the plate was
sealed and the fluorescence intensity of each sample was ed by using a Wallac
1420 ZTM plate reader nElmer) with excitation at 485 nm and emission
detection at 535 nm. Finally, the data were normalized by using the controls and
|C50-values were determined using GraphPad PrismTM (GraphPad) by fitting a
logarithmic curve to the averaged datapoints.
2.4. Cytotoxicity assay
The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells (CRL-1651) was
determined using the MTT reduction assay (T. Mossman, J. Immunol. Meth. 1983, 65,
55-63; M.V. Berridge, A.S. Tan, Arch. Biochem. Biophys. 1993, 303, 474-482). Briefly,
the method was as follows: 4000 HELA cells/well and 3400 COS-7 cells/well were
seeded and grown in 96-well microtiter plates for 24 h at 37 °C at 5% C02. fter,
time zero (T2) was determined by MTT ion (see below). The supernatant of the
remaining wells was discarded, and fresh medium and compounds in serial dilutions
(12.5, 25 and 50 (1M, triplicates; 0 uM, blank) were pipetted into the wells. After
incubation of the cells for 48 h at 37 °C at 5% C02 the supernatant was discarded
again and 100 uL MTT reagent (0.5 mg/mL in RPM|1640 and DMEM,
respectively)/we|l was added. Following incubation at 37 °C for 2-4 h the media were
aspirated and the cells were spiked (100 uL isopropanol/well). The absorbance of the
lized formazan was measured at 595 nm (OD595peptide). For each
concentration es were calculated from triplicates. The percentage of growth
was calculated as follows: peptide-OD595Tz)/(OD595blank-OD595Tz) x 100%. The
Gig, (Growth Inhibition) concentrations were calculated for each peptide by using a
trend line function for the concentrations (50, 25, 12.5 and 0 uM), the corresponding
percentages and the value 50, (=TREND (C502C0,%50:%0,50).
2.5. Hemolysis
The peptides were tested for their hemolytic activity against human red blood cells
(hRBC). Fresh hRBC were washed four times with phosphate buffered saline (PBS) and
fuged for 10 min at 3000 x g. Compounds (100 uM) were incubated with 20%
hRBC (v/v) for 1 h at 37 °C and shaking at 300 rpm. The final erythrocyte
concentration was approximately 0.9 x 109 cells/mL. A value of 0% and 100% cell lysis,
respectively, was determined by incubation of hRBC in the presence of PBS containing
0.001% acetic acid and 2.5% Triton X-100 in H20, respectively. The samples were
centrifuged, the supernatants were 8-fold diluted in PBS buffer and the l
densities (OD) were measured at 540 nm. The 100% lyses value (OD540H20) gave an
OD540 of approximately 0.5-1.0. Percent hemolysis was ated as follows:
(OD540peptide/OD540HZO) X 100%.
WO 68336
2.6. Plasma stability
The stability ofthe es in human and mouse plasma was determined by applying
the following method: 346.5 pL/deep well of y thawed human plasma (Basler
Blutspende-dienst) and mouse plasma (Harlan Sera-Lab, UK), respectively, were
spiked with 3.5 uL/well of compound dissolved in DMSO/HZO (90/10 [v/v], 1 mM,
triplicate) and incubated at 37° C. At t = 0, 15, 30, 60, 120, 240 and 1440 min ts
of 50 pL were transferred to filtration plate wells containing 150 l of 2% formic
acid in acetonitrile. Following shaking for 2 min the occurred suspensions were
ted by vacuum. 100 pL of each filtrate were transferred to a propylene microtiter
plate and dried under N2. The residual solids were reconstituted by adding 100
l of water/acetonitrile, 95/5 (v/v) + 0.2% formic acid and analyzed by LC/MS as
follows: Column: Waters, XBridge C18, mobile phases: (A) water + 0.1% formic acid
and (B) acetonitrile/water, 95/5 (v/v) + 0.1% formic acid, gradient: 5%-100% (B) in 1.8
minutes, electrospray ionization, MRM detection (triple pole). The peak areas
were determined and triplicate values are averaged. The stability is expressed in
percent of the initial value at t = 0. (tx/t0 x 100). By using the TREND function of
EXCEL (Microsoft Office 2003) TM were determined.
2.7. Plasma Protein Binding
495 pL aliquots of human plasma (Basler Blutspendedienst) as well as 495 pL aliquots
of PBS were placed in individual deepwells of a polypropylene plate (Greiner) and
spiked each with 5 pL of 1 mM solutions of peptides in 90% DMSO. After shaking the
plate for 2 min at 600 rpm 150 pL aliquots of the plasma/peptide mixtures were
transferred in triplicates to the polypropylene filter plate (10 kDa, Millipore) whereas
150 pL aliquots of the PBS/peptide mixtures were erred either to the individual
wells of the filter plate (filtered controls) or directly into the individual wells of the
ing plate (Greiner) iltered ls). The plate sandwich consisting of filter
and receiving plate was incubated for 1 h at 37 °C and subsequently centrifuged at
3220 g for 2h at 15 °C. The filtrates in the receiving plate were analysed by LC/MS as
follows: Column: Waters, XBridge C18, mobile phases: (A) water + 0.1% formic acid
and (B) acetonitrile/water, 95/5 (v/v) + 0.1% formic acid, gradient: 5%-100% (B) in
1.8 min, electrospray ionization, MRM detection (triple quadrupole). The peak areas
were determined and triplicate values are averaged. The g is expressed in
percent of the filtered and non-filtered ls by 100-(100x tr). Finally the
average of these values is calculated.
The results of the experiments described under 2.3 — 2.7 are indicated in the Tables 1,
2, 3 and 4 herein below.
2.8. Pharmacokinetic study (PK)
For the compounds of Ex. 1, Ex.2, Ex. 3, Ex. 4, Ex. 5 and Ex. 6 pharmacokinetic studies
after intravenous (iv) administration were performed.
grams (1r 20%) male CD-1 mice obtained from Charles River Laboratories
Deutschland GmbH were used. The vehicle, phosphate ed saline, was added to
give a final concentration of 0.5 mg/mL of the compound. The volume was
2 mL/kg and the compound was injected to give a final intravenous dose of 1 mg/kg.
Approximately 300-400 uL of blood was removed under light isoflurane anesthesia by
cardiac puncture at predetermined time intervals (5, 15, 30 min and 1, 2, 3, 4, hours)
and added to heparinized tubes. Plasma was d from pelleted cells upon
centrifugation and frozen at -80 °C prior to HPLC-MS analysis.
Preparation ofplasma calibration- and plasma samples
Aliquots of 50 pL each of mouse plasma of untreated aminals (”blank” mouse )
were spiked with known amounts of the compounds Ex. 1, Ex.2, Ex. 3, Ex. 4, Ex. 5 and
Ex. 6 in order to obtain 10 plasma calibration samples for each compound in the
range 1 — 4000 ng/mL. Aliquots of 50 pL each of mouse plasma from treated animals
were used as plasma study samples.
Extraction ofplasma calibration- and plasma study-samples
All plasma s were spiked with an appropriate internal standard and extracted
with acetonitrile containing 2% formic acid. Supernatants were evaporated to dryness
under nitrogen and the remaining solids reconstituted in water/acetonitrile 95/5 (v/v)
+ 0.2% formic acid.
LC—MS/MS-analysis
Extracts were then analyzed by reverse-phase chromatography (Acquity BEH C18, 100
x 2.1 mm, 1.7 pm column, Waters for Ex. 1 and Acquity HSS C18 SB, 100 x 2.1 mm, 1.8
pm column, Waters for Ex. 2, Ex. 3, Ex. 4, Ex. 5 and Ex. 6), using the following
conditions: Ex. 1, mobile phases: (A) water/acetonitrile 95/5 (v/v) + 0.1% formic acid,
(B) itrile/water 95/5 (v/v) + 0.1% formic acid, gradient: 1% (B) 001 min, 15%
(B) 01-25 min for Ex. 1 and 1% (B) 001 min, 40% (B) 01-25 min for Ex. 2, Ex. 3,
Ex. 4, Ex. 5 and Ex. 6. The detection and quantification was med by mass
spectrometry, with electrospray interface in positive mode and selective
fragmentation of analytes (4000 QTrap mass spectrometer, AB Sciex).
Pharmacokinetic evaluation
PK parameters were ated by WinNonLinTM software version 5.3 (Pharsight- A
CertaraTM Company, n View, CA 94041 USA) using a one-compartmental
model analysis. PK parameters were determined by least-square fitting of the model
to the experimental data.
The results of the ments described in 2.8 are ted in Tables 5a and 5b
herein below.
2.9. Drug loading calculations via maintainance dose rate (rate of infusion)
The drug load for an implant comprising a peptide of the invention was calculated
following the basic principles in cokinetics (see also J. Gabrielsson, D. Weiner,
acokinetics and Pharmaco-dynamics Data Analysis: Concepts and
Applications”, 4th edition, Swedish Pharmaceutical Press, olm, Sweden, 2006)
whereby the maintainance dose rate (rate of infusion, Rm) can be defined as the rate
at which a drug is to be administered to reach a steady state of a certain dose in the
plasma. The maintainance dose rate can be expressed using the ation
Rm [g/(h*kg)] = CLiV [L/(h*kg)] x Cssfiff [g/L], wherein CLiV is the clearance (i.v. — admin.)
and Cssfiff the effective concentration of the drug in the plasma at steady state
considering an efficacy margin A: Cssfiff [g/L] = A x (IC50/fu) x MW [(mol/L)*(g/mol)].
Therefore, the total amount of a drug loaded into an implant providing for a constant
effective concentration of that drug in the plasma for a certain period of time in a
subject of a certain body weight can be calculated by applying the following
correlation:
ad [g/subject] = Rm [g/(h*kg)] x duration [h] x BW [kg/subject].
The results of the calculations described in 2.9 are indicated in Table 6 herein below
and based on the data given in Tables 1, 4 and 5b. Further pre-conditions are an
efficacy margin of A = 3, a study on of 672 h (28 days) and a body weight of a
human suject of 70 kg. The glomerular filtration rate (GFR) which mainly influences
2012/060763
the clearance of the peptides is highly dependent on the species. In l, the GFR
of humans is averaged to be 107 mL/(h*kg) compared to the GFR of mouse being 840
mL/(h*kg). Therefore, the CLiV-mouse values indicated in Table 5b were allometrically
scaled by 107 mL/(h*kg)/840 mL/(h*kg) = 0.127 before employed in the above
described correlations.
3.0. HSC mobilization in mouse
For the compounds of Ex. 1 and Ex. 2 a HSC mobilization study was performed
consisting of a time-response study to assess the time of maximum zation after
dosing and a subsequent dose-response study.
Time-response study
Male C57Bl/6 mice (Janvier, France; n = 5 for Ex. 1, n = 3 for Ex. 2) received bolus i.p.
injections of Ex. 1 and Ex. 2, respectively, (5 mg/kg) dissolved in 10 pL of water per g
mouse weight ning 0.9% NaCl. Blood was withdrawn from the cheek pouch into
EDTA coated tubes for the time points 0, 0.5, 1, 2, 4, 6 and 8 hrs after administration.
The colony forming unit in culture counts (CFU-C counts) were determined by
performing a CFU-C assay as described below. The results of the time-response study
for Ex. 1 and Ex. 2 are indicated in Tables 7a and 7b.
Dose-response study
Male C57Bl/6 mice (Janvier, France; n = 5 per dose group for Ex. 1, n = 3 per dose
group for Ex. 2) received bolus i.p. ions of Ex. 1 and Ex. 2, respectively, at doses
of 0.5, 1.5, 5 and 15 mg/kg (compound dissolved in 10 pL of water per g mouse
weight containing 0.9% NaCl). Blood was collected as described above at the time of
maximum mobilization for Ex. 1 (4 h) and Ex. 2 (2 h), respectively. The results of the
dose-response study for Ex. 1 and Ex. 2 are indicated in Tables 8a and 8b.
CFU-C assay
CFU-C counts were determined by culturing aliquots of lysed peripheral blood in
standard semi-solid progenitor cell culture medium. In brief, a defined amount of
blood was washed with PBS buffer (Gibco®) containing 0.5% bovine serum albumin,
followed by red blood cell lysis in nic NH4C| buffer (Sigma) and a second wash
step. The cell pellet was resuspended in DMEM (Gibco®) containing 10% FCS,
suspended in 2 mL of commercially available, cytokine-replete methylcellulose
medium for murine cells (Cell Systems, USA), and plated in duplicate into 35 mm cell
culture dishes. CFU-C were scored after 7-8 days incubation under standard
conditions (20% Oz, saturated humidity, 5% C02, 37 °C). eral blood cellularity
was ed using an automated blood count machine (Drew Scientific).
Loglo esponse curve and ED50
The loglo dose-response curves of Ex. 1 and Ex. 2 based on the CFU/mL-values for the
doses 1.5, 5 and 15 mg/kg as indicated in Tables 8a and 8b, respectively, are shown in
Fig. 1 and fitted using the sigmoidal dose-response fitting function in GraphPad Prism,
version 5.03. Considering the curve ssions of both compounds the dose-
responses are constrained to a m response of 4000 CFU/mL. The ED50-values
indicated in Table 9 are therefore corresponding to a response of 2000 CFU/mL.
WO 68336
Table 1
Hemolysis
Cos-7 Cells at
Gl50 [pM] 100 pM
human pl. mouse pl. mouse pl.
cpd left at T1/2 [min] cpd left at
1440 min 1440 min
l%] l%]
WO 68336
Table 4
Table 5a
Ex. 1 Ex. 2 Ex. 3
i.v. route i.v. route i.v. route
Dose: 1 mg/kg Dose: 1 mg/kg Dose: 1 mg/kg
_0083
_0.25 989
i.v. route i.v. route i.v. route
Dose: 1 mg/kg Dose: 1 mg/kg Dose: 1 mg/kg
_0-083
_0-25
AUC0_C>0 [ng*h/mL] 1151 1518 1345 1196 409
1829 1575 1313 1615 1313 686
Table 6
Molecular Weight CLiv, human
(salt free), etric
MW [g/Mol] scaled)
[mL/h/kg]
192146
32.71204
83 10.7
114155
29.71166
22.91229
Table 7a
“mum-51m
CFU/mL 129 511 2208 2592 3109 1857 588
i SD 1 12 1 85 1 262 1 450 1 537 1 281 1 161
Table 7b
mummmmm
CFU/mL 242 839 1020 2894 1929 1164 373
$59 126 1148 +262 1329 1643 1151 196
Table 8a
Mann-fl[mg/kg] ] [mg/kg] [mg/kg] [mg/kg]
CFU/mL 129 974 1672 3325 3289
$59 1 12 157 i233 i310 i431
Table 8b
[mg/kg] [mg/kg] [mg/kg] [mg/kg] [mg/kg]
CFU/mL 242 1314 2894 3589
n.d.
+ SD
— 1 26 1 463 1 329 1 576
Table 9
ED50 Confidence interval
[mg/kg] 95%
Ex- 1
Claims (18)
1. A backbone cyclized peptidic compound, built up from 16 amino acid residues, of the formula 5 cyclo(-Tyr 1-His 2-Xaa 3-Cys 4-Ser 5-Ala 6-Xaa 7-Xaa 8- Arg 9-Tyr 10 -Cys 11 -Tyr 12 -Xaa 13 -Xaa 14 - DPro 15 -Pro 16 -) ( I), in which Xaa 3 is Ala; Tyr; or Tyr(Me), ) is (2S)amino-(4-methoxyphenyl)propionic acid, 10 Xaa 7 is DTyr; DTyr(Me); or DPro, DTyr(Me) is (2R)amino-(4-methoxyphenyl)propionic acid, or, Xaa 8 is Dab; or Orn(iPr), Dab is (2S)-2,4-diaminobutyric acid, Orn(iPr) is (2S)-Nω-isopropyl-2,5-diaminopentanoic acid, 15 Xaa 13 is Gln; or Glu, Xaa 14 is Lys(iPr), Lys(iPr) is (2S)-Nω-isopropyl-2,6-diaminohexanoic acid, all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues, and 20 the two –SH groups in the two eine residues Cys 4 and Cys11 are replaced by one –S-S– group, in free form or in pharmaceutically acceptable salt form.
2. A compound according to claim 1 of the formula I, in which Xaa13 is Gln, in free 25 form or in pharmaceutically acceptable salt form.
3. A nd according to claim 1 or claim 2 of the formula I in which Xaa3 is Tyr; or ), Xaa7 is DPro, Xaa8 is Orn(iPr) and Xaa13 is Gln, in free form or in pharmaceutically acceptable salt form.
4. A compound according to claim 1 or claim 2 of the a I, in which Xaa3 is Ala, Xaa7 is DTyr, Xaa8 is Dab, and Xaa13 is Gln, in free form or in pharmaceutically acceptable salt form.
5 5. A compound according to claim 1 to 3 of the formula I, in which Xaa3 is Tyr, Xaa7 is DPro, Xaa8 is Orn(iPr), and Xaa13 is Gln, in free form or in pharmaceutically able salt form.
6. A compound according to claim 1 to 3 of the formula I, in which Xaa3 is Tyr(Me), 10 Xaa 7 is DPro, Xaa8 is Orn(iPr), and Xaa13 is Gln, in free form or in pharmaceutically acceptable salt form.
7. A compound according to claim 1 or claim 2 of the formula I, in which Xaa3 is Ala, Xaa7 is DTyr(Me), Xaa8 is Orn(iPr), and Xaa13 is Gln, in free form or in 15 pharmaceutically acceptable salt form.
8. A compound according to claim 1 or claim 2 of the formula I, in which Xaa3 is Tyr, Xaa7 is DTyr, Xaa8 is Orn(iPr), and Xaa13 is Gln, in free form or in pharmaceutically acceptable salt form.
9. A nd according to claim 1 or claim 2 of the formula I, in which Xaa3 is Tyr(Me), Xaa7 is DTyr(Me), Xaa8 is r), and Xaa13 is Gln, in free form or in pharmaceutically acceptable salt form. 25
10. A compound as defined in any one of the claims 1 to 9 of the formula I, in free form or in pharmaceutically acceptable salt form, for use as a pharmaceutically active substance, particularly as substances having CXCR4 antagonizing, anti-cancer activity and/or anti-inflammatory ty and/or stem cell mobilizing activity.
11. A pharmaceutical ition comprising a compound according to any one of claims 1 to 10 of the formula I, in free form or in pharmaceutically acceptable salt form, and a pharmaceutically inert carrier, particularly in a form suitable for oral, topical, transdermal, injection, buccal or transmucosal administration such as a 5 tablet, dragee, e, solution, liquid, gel, plaster, cream, ointment, syrup, slurry, suspension, powder or suppository.
12. The use of a compound according to any one of claims 1 to 10 of the formula I, in free form or in pharmaceutically acceptable salt form, as a medicament having 10 CXCR4 antagonizing, anti-cancer activity and/or anti-inflammatory activity and/or stem cell mobilizing activity, particularly for preventing HIV infections in healthy individuals; for slowing, or halting, the viral progression in an HIV infected patient; for treating or preventing, a cancer, or an logical e, that is mediated by, or results from, CXCR4 receptor activity; for treating immunosuppression; for 15 anying the apheresis collection of peripheral blood stem cells; or for ng the mobilization of stem cells to regulate tissue repair in non-human subjects.
13. The use of a compound according to any one of claims 1 to 10 of the formula I, in free form or in pharmaceutically acceptable salt form, for the manufacture of a 20 medicament having CXCR4 antagonizing, anti-cancer activity and/or antiinflammatory ty and/or stem cell mobilizing activity, particularly for preventing HIV infections in healthy duals; for slowing, or halting, the viral progression in an HIV infected patient; for ng or preventing, a cancer, or an immunological disease, that is mediated by, or results from, CXCR4 receptor activity; for treating 25 immunosuppression; for accompanying the sis collection of peripheral blood stem cells; or for inducing the mobilization of stem cells to regulate tissue repair.
14. A process for the manufacture of a compound as defined in any one of the claims 1 to 10 of the formula I comprising the steps of (a) coupling a onalized solid support with an ected amino acid Pro, which Pro forms the basis of the amino acid residue in position 16 of the compound of the formula I; (b) removing the N-protecting group from the product of step (a); 5 (c) coupling the product of step (b) with an N-protected amino acid DPro, which DPro forms the basis of the amino acid residue in position 15 of the compound of the formula I; (d) ng the ecting group from the product of step (c); (e) adding, in a manner ous to that described in steps (c) and (d), each of 10 the desired amino acid residues in positions 14 to 1 of the compound of the formula I, one after the other, to the free amino group of the amino acid residue being, in each case, at the free end of the growing peptide chain coupled to the solid support, the desired amino acid used, in each case, in the coupling step analogous to step (c) being N-protected and any functional 15 group present in the said desired amino acid, other than the carboxy group of the alpha-amino moiety, also being ted; (f) replacing the two –SH groups in the two Cys residues in the product of step (e) by one –S-S– group, unless this –S-S– group is formed in step (j); (g) detaching the hexadecapeptide from the solid support; 20 (h) coupling the amino acid residue in position 1 of the hexadecapeptide with the amino acid residue in position 16 of the capeptide; (i) deprotecting any protected functional group present in the product of step (h); (j) replacing the two –SH groups in the two Cys residues in the product of step (i) 25 by one –S-S– group, unless this –S-S– group is formed in step (f); (k) attaching to the product of step (j) one or several isopropyl substituents if desired; (l) deprotecting any protected functional groups present in the product of step (k); and (m) converting a nd of the formula I in free form into the corresponding compound of the formula I in pharmaceutically acceptable salt form, if the desired product of the process is a compound of the formula I in pharmaceutically acceptable salt form, or converting a compound of the 5 formula I in pharmaceutically acceptable salt form into the corresponding compound of the a I in free form, if the d product of the process is a compound of the formula I in free form, or into the corresponding nd of the formula I in a different ceutically acceptable salt form, if the d product of the process is a compound of the formula I in a 10 different pharmaceutically acceptable salt form.
15. A compound according to claim 1, substantially as herein bed with reference to any one of the examples and/or figures. 15
16. A pharmaceutical composition according to claim 11, substantially as herein described with reference to any one of the examples and/or figures.
17. The use according to claim 12 or 13, substantially as herein described with reference to any one of the examples and/or figures.
18. A process according to claim 14, substantially as herein described with reference to any one of the examples and/or figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP2011059402 | 2011-06-07 | ||
EPPCT/EP2011/059402 | 2011-06-07 | ||
PCT/EP2012/060763 WO2012168336A1 (en) | 2011-06-07 | 2012-06-06 | Beta - hairpin peptidomimetics as cxc4 antagonists |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ618110A NZ618110A (en) | 2014-12-24 |
NZ618110B2 true NZ618110B2 (en) | 2015-03-25 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10363284B2 (en) | β-hairpin peptidomimetics | |
US9518092B2 (en) | Template-fixed beta-hairpin peptidomimetics with CXCR4 antagonizing activity | |
US9556231B2 (en) | Beta-hairpin peptidomimetics as CXC4 antagonists | |
EP2427476B1 (en) | Beta-hairpin peptidomimetics having cxcr4 antagonizing activity | |
US20110312879A1 (en) | Template-fixed beta-hairpin peptidomimetics with cxcr4 antagonizing activity | |
EP2718307B1 (en) | Beta-hairpin peptidomimetics as cxc4 antagonists | |
NZ618110B2 (en) | Beta - hairpin peptidomimetics as cxc4 antagonists | |
NZ702470B2 (en) | Beta-hairpin peptidomimetics |