Design, synthesis, and preliminary pharmacological evaluation of N-acyl-3-aminoglutarimides as broad-spectrum chemokine inhibitors in vitro and anti-inflammatory agents in vivo

被引：22

作者：

Fox, DJ

Reckless, J

Warren, SG

Grainger, DJ

机构：

[1] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England

[2] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 02期

关键词：

D O I：

10.1021/jm010984i

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of N-substituted 3-aminoglutarimides have been synthesized and tested for inhibitory activity against a range of chemokines in vitro and for suppression of lipopolysaccharide-induced inflammation in vivo. The results show that they represent the first class of small molecules with broad-spectrum chemokine inhibitory effects. Among the compounds studied, 10 (NR58,4) was the most potent, being active at doses between 5 and 15 nM in vitro and at 0.3 mg kg(-1) in vivo.

引用

页码：360 / 370

页数：11

共 25 条

[1] Neuroprotection in ischemia-reperfusion injury: An antiinflammatory approach using a novel broad-spectrum chemokine inhibitor [J].

Beech, JS ;

Reckless, J ;

Mosedale, DE ;

Grainger, DJ ;

Williams, SCR ;

Menon, DK .

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2001, 21 (06) :683-689

[2] Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-8 replication by antagonism of the chemokine receptor CXCR4 [J].

Bridger, GJ ;

Skerlj, RT ;

Padmanabhan, S ;

Martellucci, SA ;

Henson, GW ;

Struyf, S ;

Witvrouw, M ;

Schols, D ;

De Clercq, E .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (19) :3971-3981

[3] Thalidomide: Current and potential clinical applications [J].

Calabrese, L ;

Fleischer, AB .

AMERICAN JOURNAL OF MEDICINE, 2000, 108 (06) :487-495

[4] Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication [J].

Egberink, HF ;

De Clercq, E ;

Van Vliet, ALW ;

Balzarini, J ;

Bridger, GJ ;

Henson, G ;

Horzinek, MC ;

Schols, D .

JOURNAL OF VIROLOGY, 1999, 73 (08) :6346-6352

[5] Chemokines and disease [J].

Gerard, C ;

Rollins, BJ .

NATURE IMMUNOLOGY, 2001, 2 (02) :108-115

[6] THALIDOMIDE TERATOGENESIS - EVIDENCE FOR A TOXIC ARENE OXIDE METABOLITE [J].

GORDON, GB ;

SPIELBERG, SP ;

BLAKE, DA ;

BALASUBRAMANIAN, V .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1981, 78 (04) :2545-2548

[7]

Horuk R, 2000, MED RES REV, V20, P155, DOI 10.1002/(SICI)1098-1128(200003)20:2<155::AID-MED3>3.0.CO

[8]

2-G

[9] A SHORT HISTORY OF THALIDOMIDE EMBRYOPATHY [J].

LENZ, W .

TERATOLOGY, 1988, 38 (03) :203-215

[10] Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1 [J].

Liang, M ;

Mallari, C ;

Rosser, M ;

Ng, HP ;

May, K ;

Monahan, S ;

Bauman, JG ;

Islam, I ;

Ghannam, A ;

Buckman, B ;

Shaw, K ;

Wei, GP ;

Xu, W ;

Zhao, Z ;

Ho, E ;

Shen, J ;

Oanh, H ;

Subramanyam, B ;

Vergona, R ;

Taub, D ;

Dunning, L ;

Harvey, S ;

Snider, RM ;

Hesselgesser, J ;

Morrissey, MM ;

Perez, HD ;

Horuk, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (25) :19000-19008

← 1 2 3 →