CCR5 receptor antagonists: discovery and SAR of novel 4-hydroxypiperidine derivatives |
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Authors: | Lu Shou-Fu Chen Binglong Davey Dave Dunning Laura Jaroch Stefan May Karen Onuffer James Phillips Gary Subramanyam Babu Tseng Jih-Lie Wei Robert G Wei Ming Ye Bin |
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Affiliation: | Berlex Biosciences, 2600 Hilltop Drive, PO Box 4099, Richmond, CA 94804-0099, USA. shou-fu_lu@berlex.com |
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Abstract: | The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, 1, with an IC(50) of 840 nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative, 6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of 10h, a potent CCR5 antagonist with an IC(50) of 11 nM. |
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