Identification of a potent and orally active non-peptide C5a receptor antagonist.

Abstract

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 (125)I-labeled C5a to human neutrophils with a K(i) value of 2.2 nm. W-54011 also inhibited C5a-induced intracellular Ca(2+) mobilization, chemotaxis, and generation of reactive super oxide species in human neutrophils with IC(50) values of 3.1, 2.7, and 1.6 nm, respectively. In C5a-induced intracellular Ca(2+) mobilization assay with human neutrophils, W-54011 did not show agonistic activity at up to 10 microm 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 Ca(2+) 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.

• Authors: Hiroshi Sumichika, Kei Sakata, Noriko Sato, Sanae Takeshita, Seigo Ishibuchi, Mitsuharu Nakamura, Takao Kamahori, Syuji Ehara, Katsuhiko Itoh, Tatsuyuki Ohtsuka, Tomoko Ohbora, Tadashi Mishina, Hirotsugu Komatsu, Yoichi Naka
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 51 Pg. 49403-7 (Dec 20 2002) ISSN: 0021-9258 [Print] United States
• PMID: 12384495 (Publication Type: Journal Article)

Chemical References

• Aniline Compounds
• Antigens, CD
• N-((4-dimethylaminophenyl)methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide
• Peptides
• Reactive Oxygen Species
• Receptor, Anaphylatoxin C5a
• Receptors, Complement
• Recombinant Proteins
• Tetrahydronaphthalenes
• Calcium

Topics

• Aniline Compounds (chemistry, pharmacology)
• Animals
• Antigens, CD
• Calcium (metabolism)
• Cell Line
• Dose-Response Relationship, Drug
• Gerbillinae
• Humans
• Inflammation
• Inhibitory Concentration 50
• Kinetics
• Mice
• Mice, Inbred BALB C
• Models, Chemical
• Neutrophils (drug effects, metabolism)
• Peptides (chemistry)
• Protein Binding
• Rats
• Rats, Wistar
• Reactive Oxygen Species
• Receptor, Anaphylatoxin C5a
• Receptors, Complement (antagonists & inhibitors)
• Recombinant Proteins (metabolism)
• Species Specificity
• Tetrahydronaphthalenes (chemistry, pharmacology)
• Time Factors