title: Heteroaromatic-aminomethyl quinolones: potent and selective iNOS inhibitors.
abstract: The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studies led to identification of piperazine 22 and pyrimidine 32, both of which reduced plasma nitrates following oral dosing in a mouse lipopolysaccharide challenge assay.
authors.affiliation: Afraxis, La Jolla, CA 92037, United States.
authors.forename: Sergio G
authors.initials: SG
authors.lastname: Durón
authors.forename: Andrew
authors.initials: A
authors.lastname: Lindstrom
authors.forename: Céline
authors.initials: C
authors.lastname: Bonnefous
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
authors.forename: Kent T
authors.initials: KT
authors.lastname: Symons
authors.forename: Marciano
authors.initials: M
authors.lastname: Sablad
authors.forename: Natasha
authors.initials: N
authors.lastname: Rozenkrants
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Nahid
authors.initials: N
authors.lastname: Yazdani
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Noble
authors.forename: Peter
authors.initials: P
authors.lastname: Rix
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hassig
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D015363:Quinolones; D052247:Nitric Oxide Synthase Type II