title: Design, synthesis and characterization of a novel class of coumarin-based inhibitors of inducible nitric oxide synthase.
abstract: 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.
authors.affiliation: Internal Medicine, Sanofi-Aventis Pharmaceuticals, Bridgewater, NJ08807, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Jackson
authors.forename: Sukhveen
authors.initials: S
authors.lastname: Sahni
authors.forename: Lan
authors.initials: L
authors.lastname: Lee
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Luo
authors.forename: Thaddeus R
authors.initials: TR
authors.lastname: Nieduzak
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.forename: Yulin
authors.initials: Y
authors.lastname: Chiang
authors.forename: Nicola
authors.initials: N
authors.lastname: Collar
authors.forename: David
authors.initials: D
authors.lastname: Fink
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Abdelazize
authors.initials: A
authors.lastname: Laoui
authors.forename: Jean
authors.initials: J
authors.lastname: Merrill
authors.forename: Ray
authors.initials: R
authors.lastname: Boffey
authors.forename: Peter
authors.initials: P
authors.lastname: Crackett
authors.forename: Bryan
authors.initials: B
authors.lastname: Rees
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Guilloteau
authors.forename: Magali
authors.initials: M
authors.lastname: Mathieu
authors.forename: Sam S
authors.initials: SS
authors.lastname: Rebello
mesh_terms: 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
chemical_list: 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