Title: Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication
Authors: Skerlj, Renato ×
Bridger, Gary
Zhou, Yuanxi
Bourque, Elyse
McEachern, Ernest
Metz, Markus
Harwig, Curtis
Li, Tong-Shuang
Yang, Wen
Bogucki, David
Zhu, Yongbao
Langille, Jonathan
Veale, Duane
Ba, Tuya
Bey, Michael
Baird, Ian
Kaller, Alan
Krumpak, Maria
Leitch, David
Satori, Michael
Vocadlo, Krystyna
Guay, Danielle
Nan, Susan
Yee, Helen
Crawford, Jason
Chen, Gang
Wilson, Trevor
Carpenter, Bryon
Gauthier, David
Macfarland, Ron
Mosi, Renee
Bodart, Veronique
Wong, Rebecca
Fricker, Simon
Schols, Dominique #
Issue Date: Oct-2013
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:56 issue:20 pages:8049-8065
Abstract: 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 (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.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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