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The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds IIb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.

Titel:	Development of CXCR4 modulators based on the lead compound RB-108.
Autor/in / Beteiligte Person:	Bai, R ; Jie, X ; Sun, J ; Liang, Z ; Yoon, Y ; Feng, A ; Oum, Y ; Yu, W ; Wu, R ; Sun, B ; Salgado, E ; Xie, Y ; Shim, H
Link:	Zum Volltext
Zeitschrift:	European journal of medicinal chemistry, Jg. 173 (2019-07-01), S. 32
Veröffentlichung:	Paris : Editions Scientifiques Elsevier ; <i>Original Publication</i>: Paris, S.E.C.T. [etc.], 2019
Medientyp:	academicJournal
ISSN:	1768-3254 (electronic)
DOI:	10.1016/j.ejmech.2019.03.065
Schlagwort:	Amides chemical synthesis Amides chemistry Animals Anti-Inflammatory Agents, Non-Steroidal chemical synthesis Anti-Inflammatory Agents, Non-Steroidal chemistry Carrageenan Cell Line, Tumor Cell Proliferation drug effects Disease Models, Animal Dose-Response Relationship, Drug Female Humans Inflammation chemically induced Mice Mice, Inbred C57BL Molecular Structure Rats Rats, Sprague-Dawley Structure-Activity Relationship Amides pharmacology Anti-Inflammatory Agents, Non-Steroidal pharmacology Inflammation drug therapy Receptors, CXCR4 antagonists & inhibitors
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Eur J Med Chem] 2019 Jul 01; Vol. 173, pp. 32-43. <i>Date of Electronic Publication: </i>2019 Apr 05. MeSH Terms: Amides / pharmacology ; Anti-Inflammatory Agents, Non-Steroidal / pharmacology ; Inflammation / drug therapy ; Receptors, CXCR4 / antagonists & inhibitors ; Amides / chemical synthesis ; Amides / chemistry ; Animals ; Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal / chemistry ; Carrageenan ; Cell Line, Tumor ; Cell Proliferation / drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Humans ; Inflammation / chemically induced ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship References: Antimicrob Agents Chemother. 2000 Jun;44(6):1667-73. (PMID: 10817726) ; J Enzyme Inhib Med Chem. 2002 Apr;17(2):69-76. (PMID: 12420752) ; Nat Rev Drug Discov. 2003 Jul;2(7):581-7. (PMID: 12815382) ; Cancer Res. 2004 Jun 15;64(12):4302-8. (PMID: 15205345) ; Immunology. 2008 Nov;125(3):281-8. (PMID: 19128361) ; J Med Chem. 2010 Dec 23;53(24):8556-68. (PMID: 21105715) ; ACS Med Chem Lett. 2011 Aug 11;2(8):597-602. (PMID: 21841963) ; J Med Chem. 2012 Feb 9;55(3):977-94. (PMID: 22085380) ; PLoS One. 2012;7(4):e34038. (PMID: 22485156) ; ChemMedChem. 2013 Apr;8(4):622-32. (PMID: 23468189) ; PLoS One. 2013 Nov 07;8(11):e79768. (PMID: 24244561) ; Curr Opin Hematol. 2014 Jan;21(1):29-36. (PMID: 24275689) ; PLoS One. 2014 Apr 02;9(4):e93665. (PMID: 24695674) ; Adv Cancer Res. 2014;124:31-82. (PMID: 25287686) ; ACS Chem Biol. 2015 Mar 20;10(3):715-24. (PMID: 25398025) ; Bioorg Med Chem. 2015 Jul 15;23(14):4050-5. (PMID: 25801155) ; Eur J Med Chem. 2016 Mar 3;110:115-25. (PMID: 26820554) ; Eur J Med Chem. 2016 Aug 8;118:340-50. (PMID: 27179215) ; Sci Rep. 2016 Jul 07;6:29338. (PMID: 27385284) ; Bioorg Med Chem. 2016 Nov 1;24(21):5052-5060. (PMID: 27576294) ; Eur J Med Chem. 2017 Jan 27;126:464-475. (PMID: 27914361) ; Inflammation. 2017 Jun;40(3):937-945. (PMID: 28285461) ; Eur J Med Chem. 2017 Aug 18;136:360-371. (PMID: 28521261) ; Eur J Med Chem. 2018 Apr 25;150:195-205. (PMID: 29529500) ; Eur J Med Chem. 2018 Jun 25;154:68-90. (PMID: 29777988) ; Ann Nucl Med. 2018 Oct;32(8):503-511. (PMID: 30105558) ; Nat Med. 1998 Jan;4(1):72-7. (PMID: 9427609) Grant Information: R01 CA165306 United States CA NCI NIH HHS; T32 GM008602 United States GM NIGMS NIH HHS Contributed Indexing: Keywords: Anti-inflammation; CXCR4 modulators; Inflammatory cell recruitment; RB-108; Structural modification Substance Nomenclature: 0 (Amides) ; 0 (Anti-Inflammatory Agents, Non-Steroidal) ; 0 (CXCR4 protein, human) ; 0 (Receptors, CXCR4) ; 9000-07-1 (Carrageenan) Entry Date(s): Date Created: 20190415 Date Completed: 20190617 Latest Revision: 20200701 Update Code: 20231215 PubMed Central ID: PMC6488424

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Development of CXCR4 modulators based on the lead compound RB-108.