Antagonists of the human CCR5 receptor as anti-HIV-1 agents.: Part 2:: Structure-activity relationships for substituted 2-aryl-1-[N-(methyl)-N-(phenylsulfonyl) amino]-4-(piperidin-1-yl)butanes

被引：72

作者：

Finke, PE

Meurer, LC

Oates, B

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 02期

关键词：

D O I：

10.1016/S0960-894X(00)00639-9

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16. X=H, 3-F, 3-Cl, 3-Me). (C) 2001 Published by Elsevier Science Ltd.

引用

收藏

页码：265 / 270

页数：6

相关论文

共 22 条

[1] Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures [J].

AbdelMagid, AF ;

Carson, KG ;

Harris, BD ;

Maryanoff, CA ;

Shah, RD .

JOURNAL OF ORGANIC CHEMISTRY, 1996, 61 (11) :3849-3862

[2] Human chemokines: An update [J].

Baggiolini, M ;

Dewald, B ;

Moser, B .

ANNUAL REVIEW OF IMMUNOLOGY, 1997, 15 :675-705

[3] Chemokine receptors and HIV-1: An attractive pair? [J].

Bates, P .

CELL, 1996, 86 (01) :1-3

[4] HIV-1 entry - an expanding portal for drug discovery [J].

Blair, WS ;

Lin, PF ;

Meanwell, NA ;

Wallace, OB .

DRUG DISCOVERY TODAY, 2000, 5 (05) :183-194

[5] Host factors in the pathogenesis of HIV disease [J].

Cohen, OJ ;

Kinter, A ;

Fauci, AS .

IMMUNOLOGICAL REVIEWS, 1997, 159 :31-48

[6] IN-VIVO EMERGENCE OF HIV-1 VARIANTS RESISTANT TO MULTIPLE PROTEASE INHIBITORS [J].

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 .

NATURE, 1995, 374 (6522) :569-571

[7] Current evidence and future directions for targeting HIV entry - Therapeutic and prophylactic strategies [J].

D'Souza, MP ;

Cairns, JS ;

Plaeger, SF .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2000, 284 (02) :215-222

[8] 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 [J].

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 .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (02) :259-264

[9] A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5 [J].

Dragic, T ;

Trkola, A ;

Thompson, DAD ;

Cormier, EG ;

Kajumo, FA ;

Maxwell, E ;

Lin, SW ;

Ying, WW ;

Smith, SO ;

Sakmar, TP ;

Moore, JP .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (10) :5639-5644

[10] Host factors and the pathogenesis of HIV-induced disease [J].

Fauci, AS .

NATURE, 1996, 384 (6609) :529-534