title: Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns.
abstract: The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. nicholas.meanwell@bms.com
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Owen B
authors.initials: OB
authors.lastname: Wallace
authors.forename: Haiquan
authors.initials: H
authors.lastname: Fang
authors.forename: Henry
authors.initials: H
authors.lastname: Wang
authors.forename: Milind
authors.initials: M
authors.lastname: Deshpande
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yin
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Pearce
authors.forename: Jennifer
authors.initials: J
authors.lastname: James
authors.forename: Kap-Sun
authors.initials: KS
authors.lastname: Yeung
authors.forename: Zhilei
authors.initials: Z
authors.lastname: Qiu
authors.forename: J J
authors.initials: JJ
authors.lastname: Kim Wright
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Donald L
authors.initials: DL
authors.lastname: Tweedie
authors.forename: Suresh
authors.initials: S
authors.lastname: Yeola
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Sunanda
authors.initials: S
authors.lastname: Ranadive
authors.forename: Brett A
authors.initials: BA
authors.lastname: Robinson
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: Hwei-Gene Heidi
authors.initials: HG
authors.lastname: Wang
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D007211:Indoles