title: 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.affiliation: Pharmaceuticals Research Division, Mitsubishi Pharma Co., 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. sumichika.hiroshi@mg.m-pharma.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sumichika
authors.forename: Kei
authors.initials: K
authors.lastname: Sakata
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Sanae
authors.initials: S
authors.lastname: Takeshita
authors.forename: Seigo
authors.initials: S
authors.lastname: Ishibuchi
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Takao
authors.initials: T
authors.lastname: Kamahori
authors.forename: Syuji
authors.initials: S
authors.lastname: Ehara
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Itoh
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohbora
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mishina
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Naka
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000814:Aniline Compounds; D015703:Antigens, CD; C470794:N-((4-dimethylaminophenyl)methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide; D010455:Peptides; D017382:Reactive Oxygen Species; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011994:Recombinant Proteins; D013764:Tetrahydronaphthalenes; D002118:Calcium