title: Discovery of a novel series of 4-quinolone JNK inhibitors.
abstract: A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto, Palo Alto, CA 94304, USA. leyi.gong@sri.com
authors.forename: Leyi
authors.initials: L
authors.lastname: Gong
authors.forename: Yun-Chou
authors.initials: YC
authors.lastname: Tan
authors.forename: Genevieve
authors.initials: G
authors.lastname: Boice
authors.forename: Sarah
authors.initials: S
authors.lastname: Abbot
authors.forename: Kristen
authors.initials: K
authors.lastname: McCaleb
authors.forename: Pravin
authors.initials: P
authors.lastname: Iyer
authors.forename: Fengrong
authors.initials: F
authors.lastname: Zuo
authors.forename: Joseph
authors.initials: J
authors.lastname: Dal Porto
authors.forename: Brian
authors.initials: B
authors.lastname: Wong
authors.forename: Sue
authors.initials: S
authors.lastname: Jin
authors.forename: Alice
authors.initials: A
authors.lastname: Chang
authors.forename: Patricia
authors.initials: P
authors.lastname: Tran
authors.forename: Gary
authors.initials: G
authors.lastname: Hsieh
authors.forename: Linghao
authors.initials: L
authors.lastname: Niu
authors.forename: Ada
authors.initials: A
authors.lastname: Shao
authors.forename: Deborah
authors.initials: D
authors.lastname: Reuter
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lukacs
authors.forename: R
authors.initials: R
authors.lastname: Ursula Kammlott
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
mesh_terms: D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D042462:4-Quinolones; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases