2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease.
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).
Hays
S J
SJ
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Caprathe
B W
BW
Gilmore
J L
JL
Amin
N
N
Emmerling
M R
MR
Michael
W
W
Nadimpalli
R
R
Nath
R
R
Raser
K J
KJ
Stafford
D
D
Watson
D
D
Wang
K
K
Jaen
J C
JC
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
D010078:Oxazines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D015923:Complement C1r