title: Pyrazolo-Piperidines Exhibit Dual Inhibition of CCR5/CXCR4 HIV Entry and Reverse Transcriptase.
abstract: We report novel anti-HIV-1 agents with combined dual host-pathogen pharmacology. Lead compound 3, composed of a pyrazole-piperidine core, exhibits three concurrent mechanisms of action: (1) non-nucleoside reverse transcriptase inhibition, (2) CCR5-mediated M-tropic viral entry inhibition, and (3) CXCR4-based T-tropic viral entry inhibition that maintains native chemokine ligand binding. This discovery identifies important tool compounds for studying viral infectivity and prototype agents that block HIV-1 entry through dual chemokine receptor ligation.
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Cox
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Prosser
authors.affiliation: Bristol-Myers Squibb , Wallingford, Connecticut 06492, United States.
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Bristol-Myers Squibb , Wallingford, Connecticut 06492, United States.
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb , Wallingford, Connecticut 06492, United States.
authors.forename: Sangil
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine , Atlanta, Georgia 30310, United States.
authors.forename: Ming B
authors.initials: MB
authors.lastname: Huang
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine , Atlanta, Georgia 30310, United States.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Bond
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Bristol-Myers Squibb , Wallingford, Connecticut 06492, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wilson
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
keywords: HIV-1; chemokine receptors; multitarget drug discovery; non-nucleoside reverse transcriptase inhibitors; viral entry inhibitors