title: Identification of an Adamantyl Azaquinolone JNK Selective Inhibitor.
abstract: 3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure-activity relationship of the azaquinolone analogues leading to 4 is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-α challenge models.
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Nancy-Ellen
authors.initials: NE
authors.lastname: Haynes
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Scott
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Li C
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Jia Kui
authors.initials: JK
authors.lastname: Li
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lukacs
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Effie
authors.initials: E
authors.lastname: Tozzo
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Toni
authors.initials: T
authors.lastname: Whittard
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Brown
authors.affiliation: Hoffmann-La Roche Inc. , pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Adrian Wai-Hing
authors.initials: AW
authors.lastname: Cheung
keywords: JNK selective inhibitor; adamantyl azaquinolone; kidney disease