title: Inhibitors of HIV-1 attachment. Part 8: the effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indole-based inhibitors.
abstract: As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.
authors.affiliation: Bristol-Myers Squibb Research & Development, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA. kapsun.yeung@bms.com
authors.forename: Kap-Sun
authors.initials: KS
authors.lastname: Yeung
authors.forename: Zhilei
authors.initials: Z
authors.lastname: Qiu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yin
authors.forename: Ashok
authors.initials: A
authors.lastname: Trehan
authors.forename: Haiquan
authors.initials: H
authors.lastname: Fang
authors.forename: Bradley
authors.initials: B
authors.lastname: Pearce
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Celia J
authors.initials: CJ
authors.lastname: D'Arienzo
authors.forename: Keith
authors.initials: K
authors.lastname: Riccardi
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: Marc R
authors.initials: MR
authors.lastname: Browning
authors.forename: Steven
authors.initials: S
authors.lastname: Hansel
authors.forename: Kenneth
authors.initials: K
authors.lastname: Santone
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barker
authors.forename: Thomas
authors.initials: T
authors.lastname: Coulter
authors.forename: Ping-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D053585:Virus Attachment / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D007211:Indoles; C030374:indole