Discovery of Bioavailable 4,4-Disubstituted Piperidines as Potent Ligands of the Chemokine Receptor 5 and Inhibitors of the Human Immunodeficiency Virus-1

被引：32

作者：

Kazmierski, Wieslaw M. ^{[1
]}

Aquino, Christopher ^{[6
]}

Chauder, Brian A. ^{[6
]}

Deanda, Felix ^{[3
]}

Ferris, Robert ^{[1
]}

Jones-Hertzog, Deborah K. ^{[4
]}

Kenakin, Terrence ^{[2
]}

Koble, Cecilia S. ^{[6
]}

Watson, Christian ^{[2
]}

Wheelan, Pat ^{[5
]}

Yang, Hanbiao

Youngman, Michael ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Infect Dis Ctr Excellence Drug Discovery, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline Inc, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline Inc, Computat & Struct Chem, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline Inc, Drug Discovery IT, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline Inc, ID DMPK, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline Inc, Metab Pathways Ctr Excellence Drug Discovery, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 20期

关键词：

D O I：

10.1021/jm800598a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1 beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC(50) = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC(50) = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.

引用

页码：6538 / 6546

页数：9

共 31 条

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