5,5-trans lactone-containing inhibitors of serine proteases: identification of a novel, acylating thrombin inhibitor.
Synthesis of a variety of 5,5-trans fused lactones, related to compounds found in extracts of Lantana camara, has provided a series of novel acylating inhibitors of human thrombin, trypsin, chymotrypsin and human leucocyte elastase. The most effective thrombin inhibitor is 7 with an IC50 of 130 nM and a Kobs/[1] of 4,000 M-1 s-1.
Finch
H
H
Department of Medicinal Chemistry, GlaxoWellcome Research and Development, Stevenage, Herts., U.K. hf3736@glaxowellcome.co.uk
Pegg
N A
NA
McLaren
J
J
Lowdon
A
A
Bolton
R
R
Coote
S J
SJ
Dyer
U
U
Montana
J G
JG
Owen
M R
MR
Dowle
M
M
Buckley
D
D
Ross
B C
BC
Campbell
C
C
Dix
C
C
Mooney
C
C
Man-Tang
C
C
Patel
C
C
D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D007783:Lactones; D015842:Serine Proteinase Inhibitors; D013917:Thrombin