2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase.
A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.
Hagen
T J
TJ
Discovery Medicinal Chemistry, Searle, Monsanto, 4901 Searle Parkway, Skokie, Illinois 60077, Discovery Pharmacology, Searle, Monsanto, 800 North Lindbergh Boulevard, St. Louis, Missouri 63167, USA.
Bergmanis
A A
AA
Kramer
S W
SW
Fok
K F
KF
Schmelzer
A E
AE
Pitzele
B S
BS
Swenton
L
L
Jerome
G M
GM
Kornmeier
C M
CM
Moore
W M
WM
Branson
L F
LF
Connor
J R
JR
Manning
P T
PT
Currie
M G
MG
Hallinan
E A
EA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004790:Enzyme Induction; 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*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C114610:4-methyl-5-pentylpyrrolidin-2-imine; D004791:Enzyme Inhibitors; D007097:Imines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D011759:Pyrrolidines; D009569:Nitric Oxide; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse