title: Substituted 4,6-diaminoquinolines as inhibitors of C5a receptor binding.
abstract: The anaphylatoxin C5a is implicated in a number of inflammatory diseases. It is a highly cationic protein with 13 of 74 amino acids being either arginine or lysine. A search focusing on positively charged molecules, particularly amine-containing functionalities, led to the discovery of substituted 4,6-diaminoquinolines 1 [N,N'-bis(4-amino-2-methyl-6-quinolyl)urea] and 7 [6-N-(2-chlorocinnamoyl)-4,6-diamino-2-methylquinoline] as inhibitors of C5a receptor binding. These two compounds inhibited the binding of radiolabeled C5a to its receptor isolated from human neutrophils with IC50's = 3.3 and 12 micrograms/mL, respectively. Our efforts to enhance their potencies by chemical modification revealed a narrow profile of potency for effective C5a receptor binding inhibition.
authors.affiliation: Department of Medicinal Chemical Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: T J
authors.initials: TJ
authors.lastname: Lanza
authors.forename: P L
authors.initials: PL
authors.lastname: Durette
authors.forename: T
authors.initials: T
authors.lastname: Rollins
authors.forename: S
authors.initials: S
authors.lastname: Siciliano
authors.forename: D N
authors.initials: DN
authors.lastname: Cianciarulo
authors.forename: S V
authors.initials: SV
authors.lastname: Kobayashi
authors.forename: C G
authors.initials: CG
authors.lastname: Caldwell
authors.forename: M S
authors.initials: MS
authors.lastname: Springer
authors.forename: W K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a