title: Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like pharmacokinetic properties II. Central core replacement.
abstract: In this Letter, we describe the evolution of selective JNK3 inhibitors from 1, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs. Strong SAR was found for substitution of the naphthalene ring, as well as for inhibitors adopting different central scaffolds. Significant potency gains were appreciated by inverting the polarity of the thione of the parent triazolothione 1, resulting in potent compounds with attractive pharmacokinetic profiles.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals, South San Francisco, CA 94080, United States. jeff.neitz@gmail.com
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Karina
authors.initials: K
authors.lastname: Wong
authors.forename: Ann
authors.initials: A
authors.lastname: Qin
authors.forename: Colin
authors.initials: C
authors.lastname: Lorentzen
authors.forename: David
authors.initials: D
authors.lastname: Nakamura
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Kyle
authors.initials: K
authors.lastname: Powell
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: David
authors.initials: D
authors.lastname: Chereau
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bard
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.forename: Irene
authors.initials: I
authors.lastname: Griswold-Prenner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009281:Naphthalenes; D013871:Thiones; C031721:naphthalene; D048057:Mitogen-Activated Protein Kinase 10