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Anti-inflammatory hybrids of secondary amines and amide-sulfamide derivatives.

Abstract：

:The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells. Additionally, compound 7a blocked mice ear inflammation by 67% and suppressed the accumulation of inflammatory cells in an in vivo mouse ear edema evaluation. Western blot analyses revealed that 7a inhibited the CXCR4/CXCL12-mediated phosphorylation of Akt and p44 in a dose-dependent manner. Moreover, compound 7a had no observable cytotoxicity and displayed a favorable plasma stability in our preliminary pharmacokinetic study. These results confirmed that this is a feasible method to develop CXCR4 modulators for the regulation and reduction of inflammation.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Bai R,Sun J,Liang Z,Yoon Y,Salgado E,Feng A,Oum Y,Xie Y,Shim H

doi

10.1016/j.ejmech.2018.02.085

subject

Has Abstract

pub_date

2018-04-25 00:00:00

pages

195-205

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30228-9

journal_volume

150

pub_type

杂志文章

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