POTENT AND HIGHLY SELECTIVE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) INHIBITION BY A SERIES OF ALPHA-ANILINOPHENYLACETAMIDE DERIVATIVES TARGETED AT HIV-1 REVERSE-TRANSCRIPTASE

被引：202

作者：

PAUWELS, R ^{[1
]}

ANDRIES, K ^{[1
]}

DEBYSER, Z ^{[1
]}

VAN DAELE, P ^{[1
]}

SCHOLS, D ^{[1
]}

STOFFELS, P ^{[1
]}

DEVREESE, K ^{[1
]}

WOESTENBORGHS, R ^{[1
]}

VANDAMME, AM ^{[1
]}

JANSSEN, CGM ^{[1
]}

ANNE, J ^{[1
]}

CAUWENBERGH, G ^{[1
]}

DESMYTER, J ^{[1
]}

HEYKANTS, J ^{[1
]}

JANSSEN, MAC ^{[1
]}

DE CLERCQ, E ^{[1
]}

JANSSEN, PAJ ^{[1
]}

机构：

[1] JANSSEN RES FDN, B-2340 BEERSE, BELGIUM

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 1993年 / 90卷 / 05期

关键词：

D O I：

10.1073/pnas.90.5.1711

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In vitro evaluation of a large chemical library of pharmacologically acceptable prototype compounds in a high-capacity, cellular-based screening system has led to the discovery of another family of human immunodeficiency virus type 1 (HIV-1) inhibitors. Through optimization of a lead compound, several alpha-anilinophenylacetamide (alpha-APA) derivatives have been identified that inhibit the replication of several HIV-1 strains (III(B)/LAI, RF, NDK, MN, HE) in a variety of host cell types at concentrations that are 10,000- to 100,000-fold lower than their cytotoxic concentrations. The IC50 of the alpha-APA derivative R 89439 for HIV-1 cytopathicity in MT-4 cells was 13 nM. The median 90% inhibitory concentration (IC90) in a variety of host cells was 50-100 nM. Although these alpha-APA derivatives are active against a tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione-(TIBO)-resistant HIV-1 strain, they do not inhibit replication of HIV-2 (strains ROD and EHO) or simian immunodeficiency virus (strains Mac251, mndGB1, and agm3). An HIV-1 strain containing the Tyr181 --> Cys mutation in the reverse transcriptase region displayed reduced sensitivity. Alpha-APA derivative R 89439 inhibited virion and recombinant reverse transcriptase of HIV-1 but did not inhibit that of HIV-2. Reverse transcriptase inhibition depended upon the template/primer used. The relatively uncomplicated synthesis of R 89439, its potent anti-HIV-1 activity, and its favorable pharmacokinetic profile make R 89439 a good candidate for clinical studies.

引用

页码：1711 / 1715

页数：5

共 28 条

[1] STRUCTURE OF HIV-1 REVERSE-TRANSCRIPTASE DNA COMPLEX AT 7-A RESOLUTION SHOWING ACTIVE-SITE LOCATIONS [J].