Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV-1 Replication

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• 作者：Renato Skerlj ; Gary Bridger ; Yuanxi Zhou ; Elyse Bourque ; Ernest McEachern ; Markus Metz ; Curtis Harwig ; Tong-Shuang Li ; Wen Yang ; David Bogucki ; Yongbao Zhu ; Jonathan Langille ; Duane Veale ; Tuya Ba ; Michael Bey ; Ian Baird ; Alan Kaller ; Maria Krumpak ; David Leitch ; Michael Satori ; Krystyna Vocadlo ; Danielle Guay ; Susan Nan ; Helen Yee ; Jason Crawford ; Gang Chen ; Trevor Wilson ; Bryon Carpenter ; David Gauthier ; Ron MacFarland ; Renee Mosi ; Veronique Bodart ; Rebecca Wong ; Simon Fricker ; Dominique Schols
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：8049-8065
• 全文大小：622K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure鈥揳ctivity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.