JBC Avanti Polar Lipids

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hesselgesser, J.
Right arrow Articles by Horuk, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hesselgesser, J.
Right arrow Articles by Horuk, R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

J Biol Chem, Vol. 273, Issue 25, 15687-15692, June 19, 1998

Identification and Characterization of Small Molecule Functional Antagonists of the CCR1 Chemokine Receptor

Joseph HesselgesserDagger , Howard P. Ng§, Meina Liang§, Wei Zheng§, Karen May§, John G. Bauman§, Sean Monahan§, Imadul Islam§, Guo Ping Wei§, Ameen Ghannam§, Dennis D. Taub, Mary Rosser§, R. Michael Snider§, Michael M. Morrissey§, H. Daniel PerezDagger , and Richard HorukDagger

From the Dagger  Departments of Immunology and § Pharmaceuticals Discovery, Berlex BioSciences, Richmond, California 94806 and the  Laboratory of Immunology, NIA, National Institutes of Health, Baltimore, Maryland 21224

The CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha ) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had Ki values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitrite), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1alpha -induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1alpha - and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 µM. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1alpha , RANTES, and CCR1.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
N. Vaidehi, S. Schlyer, R. J. Trabanino, W. B. Floriano, R. Abrol, S. Sharma, M. Kochanny, S. Koovakat, L. Dunning, M. Liang, et al.
Predictions of CCR1 Chemokine Receptor Structure and BX 471 Antagonist Binding Followed by Experimental Validation
J. Biol. Chem., September 15, 2006; 281(37): 27613 - 27620.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Strasly, G. Doronzo, P. Capello, D. Valdembri, M. Arese, S. Mitola, P. Moore, G. Alessandri, M. Giovarelli, and F. Bussolino
CCL16 activates an angiogenic program in vascular endothelial cells
Blood, January 1, 2004; 103(1): 40 - 49.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Onuffer, M. A. McCarrick, L. Dunning, M. Liang, M. Rosser, G.-P. Wei, H. Ng, and R. Horuk
Structure Function Differences in Nonpeptide CCR1 Antagonists for Human and Mouse CCR1
J. Immunol., February 15, 2003; 170(4): 1910 - 1916.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Casarosa, W. M. Menge, R. Minisini, C. Otto, J. van Heteren, A. Jongejan, H. Timmerman, B. Moepps, F. Kirchhoff, T. Mertens, et al.
Identification of the First Nonpeptidergic Inverse Agonist for a Constitutively Active Viral-encoded G Protein-coupled Receptor
J. Biol. Chem., February 7, 2003; 278(7): 5172 - 5178.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Zoffmann, A. Chollet, and J.-L. Galzi
Identification of the Extracellular Loop 2 as the Point of Interaction between the N Terminus of the Chemokine MIP-1alpha and Its CCR1 Receptor
Mol. Pharmacol., September 1, 2002; 62(3): 729 - 736.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. D'AMBROSIO, M. MARIANI, P. PANINA-BORDIGNON, and F. SINIGAGLIA
Chemokines and Their Receptors Guiding T Lymphocyte Recruitment in Lung Inflammation
Am. J. Respir. Crit. Care Med., October 1, 2001; 164(7): 1266 - 1275.
[Full Text] [PDF]

Home page
 BloodHome page
C. Weber, K. S. C. Weber, C. Klier, S. Gu, R. Wank, R. Horuk, and P. J. Nelson
Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and TH1-like/CD45RO+ T cells
Blood, February 15, 2001; 97(4): 1144 - 1146.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hebert, R. Horuk, K. Matsushima, L. H. Miller, J. J. Oppenheim, and C. A. Power
International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors
Pharmacol. Rev., March 1, 2000; 52(1): 145 - 176.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Tokuda, M. Itakura, N. Onai, H. Kimura, T. Kuriyama, and K. Matsushima
Pivotal Role of CCR1-Positive Leukocytes in Bleomycin- Induced Lung Fibrosis in Mice
J. Immunol., March 1, 2000; 164(5): 2745 - 2751.
[Abstract] [Full Text] [PDF]

Home page
 Mult SclerHome page
G X Zhang, C M Baker, D L Kolson, and A M Rostami
Chemokines and chemokine receptors in the pathogenesis of multiple sclerosis
Multiple Sclerosis, February 1, 2000; 6(1): 3 - 13.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. Rosenkilde, T. N. Kledal, H. Brauner-Osborne, and T. W. Schwartz
Agonists and Inverse Agonists for the Herpesvirus 8-encoded Constitutively Active Seven-transmembrane Oncogene Product, ORF-74
J. Biol. Chem., January 8, 1999; 274(2): 956 - 961.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Mirzadegan, F. Diehl, B. Ebi, S. Bhakta, I. Polsky, D. McCarley, M. Mulkins, G. S. Weatherhead, J.-M. Lapierre, J. Dankwardt, et al.
Identification of the Binding Site for a Novel Class of CCR2b Chemokine Receptor Antagonists. BINDING TO A COMMON CHEMOKINE RECEPTOR MOTIF WITHIN THE HELICAL BUNDLE
J. Biol. Chem., August 11, 2000; 275(33): 25562 - 25571.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Liang, C. Mallari, M. Rosser, H. P. Ng, K. May, S. Monahan, J. G. Bauman, I. Islam, A. Ghannam, B. Buckman, et al.
Identification and Characterization of a Potent, Selective, and Orally Active Antagonist of the CC Chemokine Receptor-1
J. Biol. Chem., June 16, 2000; 275(25): 19000 - 19008.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. L. Elisseeva, C. M. Slupsky, M. P. Crump, I. Clark-Lewis, and B. D. Sykes
NMR Studies of Active N-terminal Peptides of Stromal Cell-derived Factor-1. STRUCTURAL BASIS FOR RECEPTOR BINDING
J. Biol. Chem., August 25, 2000; 275(35): 26799 - 26805.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. R. White, J. M. Lee, K. Dede, C. S. Imburgia, A. J. Jurewicz, G. Chan, J. A. Fornwald, D. Dhanak, L. T. Christmann, M. G. Darcy, et al.
Identification of Potent, Selective Non-peptide CC Chemokine Receptor-3 Antagonist That Inhibits Eotaxin-, Eotaxin-2-, and Monocyte Chemotactic Protein-4-induced Eosinophil Migration
J. Biol. Chem., November 17, 2000; 275(47): 36626 - 36631.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Horuk, C. Clayberger, A. M. Krensky, Z. Wang, H.-J. Grone, C. Weber, K. S. C. Weber, P. J. Nelson, K. May, M. Rosser, et al.
A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection
J. Biol. Chem., February 2, 2001; 276(6): 4199 - 4204.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Govaerts, C. Blanpain, X. Deupi, S. Ballet, J. A. Ballesteros, S. J. Wodak, G. Vassart, L. Pardo, and M. Parmentier
The TXP Motif in the Second Transmembrane Helix of CCR5. A STRUCTURAL DETERMINANT OF CHEMOKINE-INDUCED ACTIVATION
J. Biol. Chem., April 13, 2001; 276(16): 13217 - 13225.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
I. Sabroe, M. J. Peck, B. J. Van Keulen, A. Jorritsma, G. Simmons, P. R. Clapham, T. J. Williams, and J. E. Pease
A Small Molecule Antagonist of Chemokine Receptors CCR1 and CCR3. POTENT INHIBITION OF EOSINOPHIL FUNCTION AND CCR3-MEDIATED HIV-1 ENTRY
J. Biol. Chem., August 18, 2000; 275(34): 25985 - 25992.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. Dragic, A. Trkola, D. A. D. Thompson, E. G. Cormier, F. A. Kajumo, E. Maxwell, S. W. Lin, W. Ying, S. O. Smith, T. P. Sakmar, et al.
A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5
PNAS, May 9, 2000; 97(10): 5639 - 5644.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.