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

被引：10

作者：

Skerlj, Renato ^{[1
]}

Bridge, Gary ^{[3
]}

Zhou, Yuanxi ^{[3
]}

Bourque, Elyse ^{[1
]}

McEachern, Ernest ^{[3
]}

Metz, Markus ^{[1
]}

Harwig, Curtis ^{[3
]}

Li, Tong-Shuang ^{[3
]}

Yang, Wen ^{[3
]}

Bogucki, David ^{[3
]}

Zhu, Yongbao ^{[3
]}

Langille, Jonathan ^{[3
]}

Veale, Duane ^{[3
]}

Ba, Tuya ^{[3
]}

Bey, Michael ^{[3
]}

Baird, Ian ^{[3
]}

Kaller, Alan ^{[3
]}

Krumpak, Maria ^{[3
]}

Leitch, David ^{[3
]}

Satori, Michael ^{[3
]}

Vocadlo, Krystyna ^{[3
]}

Guay, Danielle ^{[3
]}

Nan, Susan ^{[3
]}

Yee, Helen ^{[3
]}

Crawford, Jason ^{[3
]}

Chen, Gang ^{[3
]}

Wilson, Trevor ^{[3
]}

Carpenter, Bryon ^{[3
]}

Gauthier, David ^{[3
]}

MacFarland, Ron ^{[3
]}

Mosi, Renee ^{[3
]}

Bodart, Veronique ^{[3
]}

Wong, Rebecca ^{[3
]}

Fricker, Simon ^{[2
]}

Schols, Dominique ^{[4
]}

机构：

[1] Sanofi, LGCR Unit, Waltham, MA 02451 USA

[2] Sanofi Co, Genzyme, Framingham, MA 01701 USA

[3] AnorMED Inc, Langley, BC V2Y 1N5, Canada

[4] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 20期

关键词：

SMALL-MOLECULE CCR5; DISCOVERY; ENTRY; BINDING; INDIVIDUALS; SCH-351125; RESISTANCE; MECHANISM; MARAVIROC;

D O I：

10.1021/jm401101p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 activity 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 (RS) 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.

引用

页码：8049 / 8065

页数：17

共 49 条

[1] Current status of chemokine receptor inhibitors in development [J].