CCR5 receptor antagonists: Discovery and SAR of novel 4-hydroxypiperidine derivatives

Optimizing the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, which is a hit from high-throughput screening (HTS), let to discover the potent 4-hydroxypiperidine derivatives as a CCR5 receptor antagonist. 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.