| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 51, 49403-49407, December 20, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From Pharmaceuticals Research Division, Mitsubishi Pharma Co.,
1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
The anaphylatoxin C5a is a potent chemotactic
factor for neutrophils and other leukocytes, and functions as an
important inflammatory mediator. Through a high capacity screening
followed by chemical optimization, we identified a novel non-peptide
C5a receptor antagonist, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1- carboxamide
hydrochloride (W-54011). W-54011 inhibited the binding of
125I-labeled C5a to human neutrophils with a
Ki value of 2.2 nM. W-54011 also
inhibited C5a-induced intracellular Ca2+ mobilization,
chemotaxis, and generation of reactive super oxide species in human
neutrophils with IC50 values of 3.1, 2.7, and 1.6 nM, respectively. In C5a-induced intracellular
Ca2+ mobilization assay with human neutrophils, W-54011 did
not show agonistic activity at up to 10 µM and shifted
rightward the concentration-response curves to C5a without depressing
the maximal responses. Examination on the species specificity of
W-54011 revealed that it was able to inhibit C5a-induced intracellular
Ca2+ mobilization in neutrophils of cynomolgus monkeys and
gerbils but not mice, rats, guinea pigs, rabbits, and dogs. In gerbils, oral administration of W-54011 (3-30 mg/kg) inhibited
C5a-induced neutropenia in a dose-dependent manner. The
present report is the first description of an orally active non-peptide
C5a receptor antagonist that could contribute to the treatment of
inflammatory diseases mediated by C5a.
Identification of a Potent and Orally Active Non-peptide C5a
Receptor Antagonist*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
81-45-963-4286; Fax: 81-45-963-3326; E-mail:
sumichika.hiroshi@mg.m-pharma.co.jp.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  R. M. Brodbeck, D. N. Cortright, A. P. Kieltyka, J. Yu, C. O. Baltazar, M. E. Buck, R. Meade, G. D. Maynard, A. Thurkauf, D.-S. Chien, et al. Identification and Characterization of NDT 9513727 [N,N-bis(1,3-Benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a Novel, Orally Bioavailable C5a Receptor Inverse Agonist J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 898 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Waters, R. M. Brodbeck, J. Steflik, J. Yu, C. Baltazar, A. E. Peck, D. Severance, L. Y. Zhang, K. Currie, B. L. Chenard, et al. Molecular Characterization of the Gerbil C5a Receptor and Identification of a Transmembrane Domain V Amino Acid That Is Crucial for Small Molecule Antagonist Interaction J. Biol. Chem., December 9, 2005; 280(49): 40617 - 40623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fujita, I. Farkas, W. Campbell, L. Baranyi, H. Okada, and N. Okada Inactivation of C5a Anaphylatoxin by a Peptide That Is Complementary to a Region of C5a J. Immunol., May 15, 2004; 172(10): 6382 - 6387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Otto, H. Hawlisch, P. N. Monk, M. Muller, A. Klos, C. L. Karp, and J. Kohl C5a Mutants Are Potent Antagonists of the C5a Receptor (CD88) and of C5L2: POSITION 69 IS THE LOCUS THAT DETERMINES AGONISM OR ANTAGONISM J. Biol. Chem., January 2, 2004; 279(1): 142 - 151. [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 |
