Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5-(7aH)-one scaffold

被引：18

作者：

Dodd, Dharmpal S.

Sheriff, Steven

Chang, ChiehYing J.

Stetsko, Dawn K.

Phillips, Linda M.

Zhang, Yingru

Launay, Michele

Potin, Dominique

Vaccaro, Wayne

Poss, Michael A.

McKinnon, Murray

Barrish, Joel C.

Suchard, Suzanne J.

Dhar, T. G. Murali

机构：

[1] Bristol Myers Squibb Pharmaceut Res Inst, Princeton, NJ 08543 USA

[2] Cerep, F-91951 Courtaboeuf, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 07期

关键词：

LFA-1; antagonists; 2,3-dihydro-1H-pyrrolizin-5-(7aH)-one; LFA-1/ICAM interaction;

D O I：

10.1016/j.bmcl.2007.01.036

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the 1-domain of LFA-1. (c) 2007 Elsevier Ltd. All rights reserved.

引用

收藏

页码：1908 / 1911

页数：4

相关论文

共 19 条

[1]

Modulating T cell responses for the treatment of psoriasis: a focus on efalizumab [J].

Cather, JC ;

Cather, JC ;

Menter, A .

EXPERT OPINION ON BIOLOGICAL THERAPY, 2003, 3 (02) :361-370

[2]

Anti-adhesion antibodies - Efalizumab, a humanized anti-CD11a monoclonal antibody [J].

Dedrick, RL ;

Walicke, P ;

Garovoy, M .

TRANSPLANT IMMUNOLOGY, 2002, 9 (2-4) :181-186

[3]

DeLano W. L., 2002, PYMOL

[4]

Determination of the absolute configuration and solution conformation of a novel disubstituted pyrrolidine acid A by vibrational circular dichroism [J].

Freedman, Teresa B. ;

Cao, Xiaolin ;

Phillips, Linda M. ;

Cheng, Peter T. W. ;

Dalterio, Richard ;

Shu, Yue-Zhong ;

Zhang, Hao ;

Zhao, Ning ;

Shukla, Rajesh B. ;

Tymiak, Adrienne ;

Gozo, Stephen K. ;

Nafie, Laurence A. ;

Gougoutas, Jack Z. .

CHIRALITY, 2006, 18 (09) :746-753

[5]

Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule [J].

Gadek, TR ;

Burdick, DJ ;

McDowell, RS ;

Stanley, MS ;

Marsters, JC ;

Paris, KJ ;

Oare, DA ;

Reynolds, ME ;

Ladner, C ;

Zioncheck, KA ;

Lee, WP ;

Gribling, P ;

Dennis, MS ;

Skelton, NJ ;

Tumas, DB ;

Clark, KR ;

Keating, SM ;

Beresini, MH ;

Tilley, JW ;

Presta, LG ;

Bodary, SC .

SCIENCE, 2002, 295 (5557) :1086-1089

[6]

The leukocyte integrins [J].

Harris, ES ;

McIntyre, TM ;

Prescott, SM ;

Zimmerman, GA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (31) :23409-23412

[7]

Mechanisms contributing to the activity of integrins on leukocytes [J].

Hogg, N ;

Henderson, R ;

Leitinger, B ;

McDowall, A ;

Porter, J ;

Stanley, P .

IMMUNOLOGICAL REVIEWS, 2002, 186 :164-171

[8]

Kelly TA, 1999, J IMMUNOL, V163, P5173

[9]

Binding site elucidation of hydantoin-based antagonists of LFA-1 using multidisciplinary technologies: Evidence for the allosteric inhibition of a protein-protein interaction [J].

Last-Barney, K ;

Davidson, W ;

Cardozo, M ;

Frye, LL ;

Grygon, CA ;

Hopkins, JL ;

Jeanfavre, DD ;

Pav, S ;

Qian, CG ;

Stevenson, JM ;

Tong, L ;

Zindell, R ;

Kelly, TA .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2001, 123 (24) :5643-5650

[10]

Inhibitors of LFA-1/ICAM-1 interaction: from monoclonal antibodies to small molecules [J].

Liu, G .

DRUGS OF THE FUTURE, 2001, 26 (08) :767-778