OPINION Chemokine receptor antagonists: overcoming developmental hurdles

被引:242
作者
Horuk, Richard [1 ]
机构
[1] Touro Univ, Vallejo, CA 94592 USA
关键词
MONOCYTE CHEMOTACTIC PROTEIN-1; DUAL ANGIOTENSIN-II; CC-CHEMOKINE; RHEUMATOID-ARTHRITIS; SMALL-MOLECULE; MULTIPLE-SCLEROSIS; PERIPHERAL-BLOOD; ALLERGIC ENCEPHALOMYELITIS; DIFFERENTIAL EXPRESSION; COUPLED RECEPTORS;
D O I
10.1038/nrd2734
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Chemokine receptors have a key role in the pathogenesis of auto immune diseases, inflammation and viral infection. However, with the exception of selective CCR5 antagonists for HIV, the promise of obtaining new therapeutics related to chemokine receptors has not yet been realized. This article highlights some of the recent failures in the clinical trials of chemokine receptor antagonists and explores possible reasons as to why this might have occurred. Such reasons include the lack of predictability of animal models and redundancy of the target. A potential solution could be to develop drugs that target more than one receptor - known as polypharmacology - which could be a novel way to generate effective therapeutics.
引用
收藏
页码:23 / 33
页数:11
相关论文
共 119 条
  • [1] 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors
    Allegretti, M
    Bertini, R
    Cesta, MC
    Bizzarri, C
    Di Bitondo, R
    Di Cioccio, V
    Galliera, E
    Berdini, V
    Topai, A
    Zampella, G
    Russo, V
    Di Bello, N
    Nano, G
    Nicolini, L
    Locati, M
    Fantucci, P
    Florio, S
    Colotta, F
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (13) : 4312 - 4331
  • [2] Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo
    Amat, M.
    Benjamim, C. F.
    Williams, L. M.
    Prats, N.
    Terricabras, E.
    Beleta, J.
    Kunkel, S. L.
    Godessart, N.
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 2006, 149 (06) : 666 - 675
  • [3] A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation
    Anders, HJ
    Vielhauer, V
    Frink, M
    Linde, Y
    Cohen, CD
    Blattner, SM
    Kretzler, M
    Strutz, F
    Mack, M
    Gröne, HJ
    Onuffer, J
    Horuk, R
    Nelson, PJ
    Schlöndorff, D
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (02) : 251 - 259
  • [4] A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity
    Baba, M
    Nishimura, O
    Kanzaki, N
    Okamoto, M
    Sawada, H
    Iizawa, Y
    Shiraishi, M
    Aramaki, Y
    Okonogi, K
    Ogawa, Y
    Meguro, K
    Fujino, M
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) : 5698 - 5703
  • [5] Bacon K, 2002, J INTERF CYTOK RES, V22, P1067
  • [6] Chemokines and leukocyte traffic
    Baggiolini, M
    [J]. NATURE, 1998, 392 (6676) : 565 - 568
  • [7] Beaulieu A, 2006, ANN RHEUM DIS, V65, P175
  • [8] Berry K., 2004, Inflamm. Res, V53, pS222
  • [9] The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle
    Blanpain, C
    Doranz, BJ
    Bondue, A
    Govaerts, C
    De Leener, A
    Vassart, G
    Doms, RW
    Proudfoot, A
    Parmentier, M
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (07) : 5179 - 5187
  • [10] Animal models of psoriasis
    Boehncke, Wolf-Henning
    Schoen, Michael P.
    [J]. CLINICS IN DERMATOLOGY, 2007, 25 (06) : 596 - 605