Design, synthesis and characterization of a novel class of coumarin-based inhibitors of inducible nitric oxide synthase.
Inducible nitric oxide synthase (iNOS) has been implicated in various central and peripheral pathophysiological diseases. Our high throughput screening initially identified a weak inhibitor of iNOS, thiocoumarin 13. From this lead, a number of potent derivatives were prepared that demonstrate favorable potency, selectivity and kinetics. Compound 30 has an IC50 of 60 nM for mouse iNOS and 185-fold and 9-fold selectivity for bovine eNOS and rat nNOS, respectively. In cellular assays for iNOS, this compound has micromolar potency. Furthermore, two compounds (16 and 30) demonstrate a reasonable pharmacokinetic profile in rodents. The synthesis, SAR, and biological activity of this novel class of compounds is described.
Jackson
Sharon A
SA
Internal Medicine, Sanofi-Aventis Pharmaceuticals, Bridgewater, NJ08807, USA.
Sahni
Sukhveen
S
Lee
Lan
L
Luo
Yongyi
Y
Nieduzak
Thaddeus R
TR
Liang
Guyan
G
Chiang
Yulin
Y
Collar
Nicola
N
Fink
David
D
He
Wei
W
Laoui
Abdelazize
A
Merrill
Jean
J
Boffey
Ray
R
Crackett
Peter
P
Rees
Bryan
B
Wong
Melanie
M
Guilloteau
Jean-Pierre
JP
Mathieu
Magali
M
Rebello
Sam S
SS
D000818:Animals; D003374:Coumarins / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D003374:Coumarins; D004791:Enzyme Inhibitors; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat