title: Biological and Structural Characterization of Rotamers of C-C Chemokine Receptor Type 5 (CCR5) Inhibitor GSK214096.
abstract: We recently reported the discovery of preclinical CCR5 inhibitor GSK214096, 1 (J. Med. Chem. 2011, 54, 756). Detailed characterization of 1 revealed that it exists as a mixture of four separable atropisomers A-D. The two slow-interconverting pairs of rotamers A + B and C + D were separated and further characterized. HIV and CCR5-mediated chemotaxis data strongly suggest that the antiviral potency of 1 is due to rotamers A + B and not C + D. Furthermore, integrated UV, vibrational circular dichroism VCD and computational approach allowed to determine the M chirality in C + D (and P chirality in A + B). These findings imply additional avenues to be pursued toward new CCR5 antagonists.
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Danehower
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ferris
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Vassil
authors.initials: V
authors.lastname: Elitzin
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Minick
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sharp
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Stewart
authors.affiliation: Infectious Diseases TAU and Platform Technology and Science, GlaxoSmithKline , Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Manon
authors.initials: M
authors.lastname: Villeneuve
keywords: CCR5; GSK214096; HIV inhibitor; antagonist; atropisomer; chemokine; entry inhibitor