- Synthesis of [ω-3H-MeBmt1]-cyclosporin A
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[3H]-Cyclosporin A labeled at the first amino acid ([ω-3H-MeBmt1]CS) has been prepared by tritium gas hydrogenolysis of [O-acetyl-ω-bromo- MeBmt1]CS followed by deprotection with methanolic sodium methoxide. The requisite bromo intermediate was prepared by bromination of [O-acetyl- MeBmt1]CS with N-bromosuccinimide. After synthesis and purification, 2.45 m8 of [ω-3H-MeBmt1]CS with a total activity of 327 MBq were produced with a radiochemical purity >97%, and specific activity of 160 GBq/mmol (4.3 Ci/mmol).
- Cerny, Bohuslav,Jegorov, Alexandr,Polivkova, Jana,Sedmera, Petr,Havlicek, Vladimir
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Read Online
- Semisynthetic Di- and Tri-Functionalized Non-Immunosuppressive Cyclosporin A Derivatives as Potential Anti-HIV 1 Drugs
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A regio- and stereoselective synthesis of original semi-synthetic di- and tri-functionalized non-immunosuppressive cyclosporins by way of a Barton ester decarboxylation and a C-thioalkylation starting from cyclosporin A (CsA) and [4′-hydroxy-MeLeu]4-CsA is described.
- Carry, Jean-Christophe,Evers, Michel,Barrière, Jean-Claude,Bashiardes, Georges,Bensoussan, Claude,Gueguen, Jean-Christophe,Dereu, Norbert,Filoche, Bruno,Sablé, Serge,Vuilhorgne, Marc,Mignani, Serge
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- Development of a practical process for the opening of macrocyclic Cyclosporin a and amino acid deletion
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A practical and robust process for the derivatization of Cyclosporin A was demonstrated. The processes rely on the opening of Cyclosporin A and removal of amino acid fragments via Edman degradation, with the isolation of crystalline tetrafluoroboric salts of the corresponding acyclic polypeptides.
- Riss, Bernard,Grandeury, Arnaud,Gut, Thorsten,Seeger-Weibel, Manuela,Zuercher, Christian,Li, Jinjing,Gallou, Fabrice
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- Oligopeptide cyclophilin inhibitors: A reassessment
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Potent cyclophilin A (CypA) inhibitors such as non-immunosuppressive cyclosporin A (CsA) derivatives have been already used in clinical trials in patients with viral infections. CypA is a peptidyl prolyl cis/trans isomerase (PPIase) that catalyzes slow prolyl bond cis/trans interconversions of the backbone of substrate peptides and proteins. In this study we investigate whether the notoriously low affinity inhibitory interaction of linear proline-containing peptides with the active site of CypA can be increased through a combination of a high cis/trans ratio and a negatively charged C-terminus as has been recently reported for Trp-Gly-Pro. Surprisingly, isothermal titration calorimetry did not reveal formation of an inhibitory CypA/Trp-Gly-Pro complex previously described within a complex stability range similar to CsA, a nanomolar CypA inhibitor. Moreover, despite of cis content of 41% at pH 7.5 Trp-Gly-Pro cannot inhibit CypA-catalyzed standard substrate isomerization up to high micromolar concentrations. However, in the context of the CsA framework a net charge of -7 clustered at the amino acid side chain of position 1 resulted in slightly improved CypA inhibition.
- Schumann, Michael,Jahreis, Günther,Kahlert, Viktoria,Lücke, Christian,Fischer, Gunter
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Read Online
- Targeting Extracellular Cyclophilin A via an Albumin-Binding Cyclosporine A Analogue
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An albumin-binding CsA analogue 4MCsA was achieved by attachment of a thiol-reactive maleimide group at the side-chain of P4 position of CsA derivative. 4MCsA was semi-synthesized from CsA, and the cell-impermeability of albumin-4MCsA was detected by mass spectrometry and a competitive flow cytometry. 4MCsA exhibits inhibition of chemotaxis activity and inflammation by targeting extracellular CypA without immunosuppressive effect and cellular toxicity. These combined results suggested that 4MCsA can be restricted extracellularly through covalently binding to Cys34 of albumin with its maleimide group, and regulate the functions of cyclophilin A extracellularly.
- Liu, Si-Yu,Zhang, Qing-Zhou,Hu, Min-Qiang,Li, Feng-Xia,Fu, Jia-Miao,Zhu, Zhen-Dong,Li, Qin-Kai,Yang, Zhen,Quan, Jun-Min
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supporting information
p. 3649 - 3652
(2021/10/12)
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- Synthesis and characterization of bodipy-FL-cyclosporine a as a substrate for multidrug resistance-linked P-glycoprotein (ABCB1)
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Fluorescent conjugates of drugs can be used to study cellular functions and pharmacology. These compounds interact with proteins as substrates or inhibitors, helping in the development of unique fluorescence-based methods to study in vivo localization and
- Sajid, Andaleeb,Raju, Natarajan,Lusvarghi, Sabrina,Vahedi, Shahrooz,Swenson, Rolf E.,Ambudkar, Suresh V.
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p. 1013 - 1023
(2019/10/01)
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- NOVEL CYCLOSPORIN DERIVATIVES AND USES THEREOF
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A compound of the Formula (I) is disclosed: (I) or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification. Also described are a pharmaceutical composition comprising the same and a method for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, lung, and liver, and kindey diseases, and hair loss using the same.
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Paragraph 0170
(2017/12/18)
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- CYCLOSPORIN ANALOGUES FOR PREVENTING OR TREATING HEPATITIS C INFECTION
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The present invention relates to cyclosporin analogues having antiviral activity against HCV and useful in the treatment of HCV infections. More particularly, the invention relates to novel cyclosporin analogue compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
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Paragraph 0390; 0391
(2016/03/14)
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- Cyclosporin derivatives for the treatment and prevention of a viral infection
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The present invention relates to a compound of the formula (I): or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing a viral infection using the same.
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Page/Page column 37; 75
(2016/01/09)
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- NOVEL CYCLOSPORIN DERIVATIVES AND USES THEREOF
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The present invention relates to a compound of the Formula (I)): or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, and hair loss.
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Paragraph 0356-0357
(2014/09/29)
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- Anti-inflammatory effects of extracellular cyclosporins are exclusively mediated by CD147
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Leukocyte trafficking and recruitment is a critical process in host immune surveillance and in inflammatory diseases. Extracellular cyclophilins (eCyps) have been identified as a novel class of chemotactic mediators. The impact of eCyp/CD147 interactions for the recruitment of leukocytes during inflammation was analyzed using a structurally simplified cell-impermeable eCyp inhibitor. This compound was highly effective at inhibiting leukocyte migration toward CypA in vitro as well as in the recruitment of leukocytes during inflammation in a mouse model of experimentally induced peritonitis and delayed-type hypersensitivity reaction. By using CD147-/- mice in combination with the cell-impermeable eCyp inhibitor, we were able to show that the action of eCyps in inflammation is exclusively mediated by interaction with CD147. Our findings suggest that blocking eCyps may be an effective therapeutic target for reducing inflammatory diseases associated with leukocyte recruitment.
- Malesevic, Miroslav,Gutknecht, Danny,Prell, Erik,Klein, Claudia,Schumann, Michael,Nowak, Romana A.,Simon, Jan C.,Schiene-Fischer, Cordelia,Saalbach, Anja
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p. 7302 - 7311
(2013/10/21)
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- Chemical tagging of a drug target using 5-sulfonyl tetrazole
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Irreversible modification is one of the most promising strategies to identify cellular receptors of bioactive small molecules. Here we report that receptor proteins can be chemically tagged using a 5-sulfonyl tetrazole probe. 5-Sulfonyl tetrazole easily a
- Otsuki, Satsuki,Nishimura, Shinichi,Takabatake, Hisae,Nakajima, Kozue,Takasu, Yasuaki,Yagura, Toru,Sakai, Yuki,Hattori, Akira,Kakeya, Hideaki
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supporting information
p. 1608 - 1611
(2013/04/10)
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- Cyclosporin Derivatives
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A cyclosporin derivative of general Formula (I) or a pharmaceutically compatible salt thereof, which have a pharmaceutical effectiveness, for example in the case of chronic inflammatory diseases. The cyclosporin derivatives are preferably free from a peptide section capable of passing through the membrane of a biological cell.
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Page/Page column 15-16
(2012/08/08)
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- Organozirconium chemistry on cyclosporin: A novel process for the highly stereoselective synthesis of (E)-ISA247 (voclosporin) and close analogues
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Application of organozirconium chemistry to cyclosporin has led to the development of a novel process for the highly stereoselective synthesis of the E-isomer of ISA247 (voclosporin), which is a potent immunosuppressive agent currently in late stage human clinical trials for treatment of psoriasis, prevention of kidney transplant rejection, and ophthalmic indications. Synthesis of deuterated analogues of ISA247 and a cyclosporin triene analogue using the same methodology is also described. Georg Thieme Verlag Stuttgart. New York.
- Maeng, Jun-Ho,Yang, Zhicai,Manning, David D.,Masih, Liaqat,Cao, Yeyu,Pattamana, Kevin G.,Bois, Frederic,Molino, Bruce F.
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experimental part
p. 63 - 68
(2012/04/10)
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- Synthesis and biological evaluation of [D-lysine]8cyclosporin A analogs as potential anti-HCV agents
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An efficient synthesis of [d-lysine]8cyclosporin A has been developed. Several analogs of [d-lysine]8cyclosporin A have been synthesized and show promising anti-HCV activity, particularly compounds 39 and 43, which each exhibit an anti-HCV EC50 200 nM, and are each ≥50-fold less immunosuppressive than cyclosporin A.
- Scribner, Andrew,Houck, David,Huang, Zhuhui,Mosier, Sarah,Peel, Michael,Scorneaux, Bernard
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scheme or table
p. 6542 - 6546
(2010/12/20)
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- Use of cyclosporin alkene analogues for preventing or treating viral-induced disorders
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The present invention relates to methods of preventing or treating a mammal with a viral-induced disorder. The method involves administering to the mammal a therapeutically effective amount of a compound represented by Formula I, as shown below: or a phar
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Page/Page column 15
(2008/06/13)
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- Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders
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The present invention relates to methods of preventing or treating a mammal with a viral-induced disorder. The method involves administering to the mammal a therapeutically effective amount of a compound represented by Formnula I, as shown below: or a pharmaceutically acceptable salt thereof, with X, R0, and R1 defined herein, under conditions effective to prevent or treat the viral-induced disorder.
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Page/Page column 7; 12-13
(2010/11/28)
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- Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
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The present invention relates to methods of preventing or treating a mammal with a viral-induced disorder. The method involves administering to the mammal a therapeutically effective amount of a compound represented by Formula I, as shown below: or a phar
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Page/Page column 11
(2010/11/28)
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- Novel cyclosporin alkynes and their utility as pharmaceutical agents
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The compounds of the present invention are represented by the chemical structure found in Formula I: or a pharmaceutically acceptable salt thereof, with X, R0, and R1 defined herein.
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Page/Page column 10-11
(2008/06/13)
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- Novel cyclosporin analogues and their pharmaceutical uses
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The compounds of the present invention are represented by Formula I, as shown below: or a pharmaceutically acceptable salt thereof, with X, R0, R1, and R2 defined herein.
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Page/Page column 14
(2008/06/13)
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- USE OF [D-MEALA]3-[ETVAL]4-CYCLOSPORIN FOR THE TREATMENT OF HEPATITIS C INFECTION AND PHARMACEUTICAL COMPOSITION COMPRISING SAID [D-MEALA]3-[ETVAL]4-CYCLOSPORIN
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This invention relates to the use in the treatment of HCV infection, either as single active agents or in combination with another active agent, of a cyclosporin having increased cyclophilin binding activity and essentially lacking immunosuppressive activ
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Page/Page column 21
(2008/06/13)
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- Cyclosporin derivatives for the treatment of immune disorders
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The present invention relates to a cyclosporin analog of the following formula (I) or a pro-drug or pharmaceutically acceptable salt thereof: wherein A is of the formula: where Q, W, X, Y, and Z are defined herein. In a second embodiment, the present inve
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Page/Page column 22
(2008/06/13)
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