title: CCR5 receptor antagonists: discovery and SAR of novel 4-hydroxypiperidine derivatives.
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.
authors.affiliation: Berlex Biosciences, 2600 Hilltop Drive, PO Box 4099, Richmond, CA 94804-0099, USA. shou-fu_lu@berlex.com
authors.forename: Shou-Fu
authors.initials: SF
authors.lastname: Lu
authors.forename: Binglong
authors.initials: B
authors.lastname: Chen
authors.forename: Dave
authors.initials: D
authors.lastname: Davey
authors.forename: Laura
authors.initials: L
authors.lastname: Dunning
authors.forename: Stefan
authors.initials: S
authors.lastname: Jaroch
authors.forename: Karen
authors.initials: K
authors.lastname: May
authors.forename: James
authors.initials: J
authors.lastname: Onuffer
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Jih-Lie
authors.initials: JL
authors.lastname: Tseng
authors.forename: Robert G
authors.initials: RG
authors.lastname: Wei
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection
chemical_list: D065100:CCR5 Receptor Antagonists; D010880:Piperidines