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

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• 作者：Wieslaw M. Kazmierski ; Christopher Aquino ; Brian A. Chauder ; Felix Deanda ; Robert Ferris ; Deborah K. Jones-Hertzog ; Terrence Kenakin ; Cecilia S. Koble ; Christian Watson ; Pat Wheelan ; Hanbiao Yang ; Mich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 23, 2008
• 年：2008
• 卷：51
• 期：20
• 页码：6538-6546
• 全文大小：257K
• 年卷期：v.51,no.20(October 23, 2008)
• ISSN：1520-4804

文摘

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the ¹²⁵I-[MIP-1β] 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 (pIC₅₀ = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC₅₀ = 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.