Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 1: Discovery and initial structure-activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes

被引:88
作者
Dorn, CP
Finke, PE
Oates, B
Budhu, RJ
Mills, SG
MacCoss, M
Malkowitz, L
Springer, MS
Daugherty, BL
Gould, SL
DeMartino, JA
Siciliano, SJ
Carella, A
Carver, G
Holmes, K
Danzeisen, R
Hazuda, D
Kessler, J
Lineberger, J
Miller, M
Schleif, WA
Emini, EA
机构
[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Immunol Res, Rahway, NJ 07065 USA
[3] Merck Res Labs, Dept Antiviral Res, W Point, PA 19486 USA
关键词
D O I
10.1016/S0960-894X(00)00637-5
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)- 1-[N-(methyl)-N-(phenylsulfonyl)amino]-4,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure-activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment. (C) 2001 Published by Elsevier Science Ltd.
引用
收藏
页码:259 / 264
页数:6
相关论文
共 33 条
  • [1] Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures
    AbdelMagid, AF
    Carson, KG
    Harris, BD
    Maryanoff, CA
    Shah, RD
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 1996, 61 (11) : 3849 - 3862
  • [2] CC CKRS: A RANTES, MIP-1 alpha, MIP-1 beta receptor as a fusion cofactor for macrophage-tropic HIV-1
    Alkhatib, G
    Combadiere, C
    Broder, CC
    Feng, Y
    Kennedy, PE
    Murphy, PM
    Berger, EA
    [J]. SCIENCE, 1996, 272 (5270) : 1955 - 1958
  • [3] Human chemokines: An update
    Baggiolini, M
    Dewald, B
    Moser, B
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 1997, 15 : 675 - 705
  • [4] CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis
    Barcellos, LF
    Schito, AM
    Rimmler, JB
    Vittinghoff, E
    Shih, A
    Lincoln, R
    Callier, S
    Elkins, MK
    Goodkin, DE
    Haines, JL
    Pericak-Vance, MA
    Hauser, SL
    Oksenberg, JR
    [J]. IMMUNOGENETICS, 2000, 51 (4-5) : 281 - 288
  • [5] Chemokine receptors and HIV-1: An attractive pair?
    Bates, P
    [J]. CELL, 1996, 86 (01) : 1 - 3
  • [6] HIV-1 entry - an expanding portal for drug discovery
    Blair, WS
    Lin, PF
    Meanwell, NA
    Wallace, OB
    [J]. DRUG DISCOVERY TODAY, 2000, 5 (05) : 183 - 194
  • [7] The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates
    Choe, H
    Farzan, M
    Sun, Y
    Sullivan, N
    Rollins, B
    Ponath, PD
    Wu, LJ
    Mackay, CR
    LaRosa, G
    Newman, W
    Gerard, N
    Gerard, C
    Sodroski, J
    [J]. CELL, 1996, 85 (07) : 1135 - 1148
  • [8] IDENTIFICATION OF RANTES, MIP-1-ALPHA, AND MIP-1-BETA AS THE MAJOR HIV-SUPPRESSIVE FACTORS PRODUCED BY CD8(+) T-CELLS
    COCCHI, F
    DEVICO, AL
    GARZINODEMO, A
    ARYA, SK
    GALLO, RC
    LUSSO, P
    [J]. SCIENCE, 1995, 270 (5243) : 1811 - 1815
  • [9] Host factors in the pathogenesis of HIV disease
    Cohen, OJ
    Kinter, A
    Fauci, AS
    [J]. IMMUNOLOGICAL REVIEWS, 1997, 159 : 31 - 48
  • [10] IN-VIVO EMERGENCE OF HIV-1 VARIANTS RESISTANT TO MULTIPLE PROTEASE INHIBITORS
    CONDRA, JH
    SCHLEIF, WA
    BLAHY, OM
    GABRYELSKI, LJ
    GRAHAM, DJ
    QUINTERO, JC
    RHODES, A
    ROBBINS, HL
    ROTH, E
    SHIVAPRAKASH, M
    TITUS, D
    YANG, T
    TEPPLER, H
    SQUIRES, KE
    DEUTSCH, PJ
    EMINI, EA
    [J]. NATURE, 1995, 374 (6522) : 569 - 571