title: 2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease.
abstract: A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement activation by beta-amyloid may represent a major contributing pathway to the neuropathology of Alzheimer's disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show improved potency compared to the reference compound FUT-175. Many of these active compounds also possess increased selectivity for C1r compared to trypsin and enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hays
authors.forename: B W
authors.initials: BW
authors.lastname: Caprathe
authors.forename: J L
authors.initials: JL
authors.lastname: Gilmore
authors.forename: N
authors.initials: N
authors.lastname: Amin
authors.forename: M R
authors.initials: MR
authors.lastname: Emmerling
authors.forename: W
authors.initials: W
authors.lastname: Michael
authors.forename: R
authors.initials: R
authors.lastname: Nadimpalli
authors.forename: R
authors.initials: R
authors.lastname: Nath
authors.forename: K J
authors.initials: KJ
authors.lastname: Raser
authors.forename: D
authors.initials: D
authors.lastname: Stafford
authors.forename: D
authors.initials: D
authors.lastname: Watson
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: J C
authors.initials: JC
authors.lastname: Jaen
mesh_terms: D015923:Complement C1r / Q000037:antagonists & inhibitors*; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010078:Oxazines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D015923:Complement C1r