title: Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) inhibitors.
abstract: Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3 inhibitor (IC(50)=40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration properties. With these properties, 13a is considered a potential candidate for in vivo evaluation.
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: He
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.forename: Xinyi
authors.initials: X
authors.lastname: Song
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Romain
authors.initials: R
authors.lastname: Noel
authors.forename: Derek
authors.initials: D
authors.lastname: Duckett
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Ling
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Susan
authors.initials: S
authors.lastname: Khan
authors.forename: Marcel
authors.initials: M
authors.lastname: Koenig
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
mesh_terms: D001921:Brain / Q000378:metabolism; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D048031:JNK Mitogen-Activated Protein Kinases