Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms.
A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 microM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
Webber
R K
RK
Department of Discovery Medicinal Chemistry, G. D. Searle Research and Development, Monsanto Company, St. Louis, Missouri 63198, USA.
Metz
S
S
Moore
W M
WM
Connor
J R
JR
Currie
M G
MG
Fok
K F
KF
Hagen
T J
TJ
Hansen
D W
DW
Jerome
G M
GM
Manning
P T
PT
Pitzele
B S
BS
Toth
M V
MV
Trivedi
M
M
Zupec
M E
ME
Tjoeng
F S
FS
D000818:Animals; D002531:Cerebellum / Q000201:enzymology; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009474:Neurons / Q000201:enzymology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000097:blood; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007097:Imines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D010880:Piperidines; D011994:Recombinant Proteins; D019001:Nitric Oxide Synthase