Novel, potent and bioavailable CCR5 chemokine receptor small-molecule antagonists for HIV therapy: Scaffold discovery and addressing hERG ion channel affinity in the process of optimizing potency and bioavailability

MEDI 297

Wieslaw Kazmierski, wieslaw.m.kazmierski@gsk.com, Don L. Anderson, Chris J. Aquino, Neil Bifulco, Larry R Boone, Eric E. Boros, Brian A. Chauder, Pek Y. Chong, Maosheng Duan, Robert G. Ferris, Terrence P. Kenakin, Cecilia S. Koble, Daniel G. Lang, Ed McLean, Margaret S. McIntyre, Jennifer P. Peckham, Andrew Spaltenstein, Angilique C. Svolto, James B. Thompson, Hanbiao Young, Michael K. Youngman, and Patricia J. Wheelan. GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709
The CCR5 chemokine receptor is used as cellular gateway by cell-infecting non-syncytia-forming, macrophage-tropic HIV-1. Several small-molecule CCR5 antagonists are in the clinic for HIV therapy. This presentation will detail the design and discovery of several GSK CCR5 scaffolds and optimization of the lead 4,4-disubstituted piperidine-based series. Key SAR findings allowing to separate the binding to CCR5 from undesirable interactions with hERG ion channel will be presented. Final fine tuning of PK, hERG and antiviral properties was accomplished with a unique combination of R, X and Y, yielding candidates suitable for further development. Scale-up chemistry, SAR and preclinical data will also be presented.

 

General Oral Session
1:30 PM-4:50 PM, Tuesday, 12 September 2006 Moscone Center -- Room 103, Oral

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006