Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.
Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.
Macdonald
S J
SJ
Medical Chemistry 2, Glaxo Wellcome Medicines Research Centre, Stevenage, UK. sjfm5947@glaxowellcome.co.uk
Dowle
M D
MD
Harrison
L A
LA
Spooner
J E
JE
Shah
P
P
Johnson
M R
MR
Inglis
G G
GG
Clarke
G D
GD
Belton
D J
DJ
Smith
R A
RA
Molloy
C R
CR
Dixon
M
M
Murkitt
G
G
Godward
R E
RE
Skarzynski
T
T
Singh
O M
OM
Kumar
K A
KA
Hodgson
S T
ST
McDonald
E
E
Hardy
G W
GW
Finch
H
H
Humphreys
D C
DC
Fleetwood
G
G
D000215:Acylation; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013552:Swine
D004791:Enzyme Inhibitors; D007769:Lactams; D011759:Pyrrolidines; D019272:Leukocyte Elastase