CCR5 receptor antagonists: discovery and SAR of novel 4-hydroxypiperidine derivatives.
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.
Lu
Shou-Fu
SF
Berlex Biosciences, 2600 Hilltop Drive, PO Box 4099, Richmond, CA 94804-0099, USA. shou-fu_lu@berlex.com
Chen
Binglong
B
Davey
Dave
D
Dunning
Laura
L
Jaroch
Stefan
S
May
Karen
K
Onuffer
James
J
Phillips
Gary
G
Subramanyam
Babu
B
Tseng
Jih-Lie
JL
Wei
Robert G
RG
Wei
Ming
M
Ye
Bin
B
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
D065100:CCR5 Receptor Antagonists; D010880:Piperidines