title: Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.
abstract: The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
authors.affiliation: Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States. simeon.bowers@elan.com
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: R
authors.initials: R
authors.lastname: Jeffrey Neitz
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sealy
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: David
authors.initials: D
authors.lastname: Quincy
authors.forename: Brian
authors.initials: B
authors.lastname: Peterson
authors.forename: Wayman
authors.initials: W
authors.lastname: Chan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Gergely
authors.initials: G
authors.lastname: Tóth
authors.forename: Hu
authors.initials: H
authors.lastname: Pan
authors.forename: May
authors.initials: M
authors.lastname: Lin
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Heather
authors.initials: H
authors.lastname: Zhang
authors.forename: Linda
authors.initials: L
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Dryer
authors.forename: Bhushan
authors.initials: B
authors.lastname: Samant
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Karina
authors.initials: K
authors.lastname: Wong
authors.forename: Colin
authors.initials: C
authors.lastname: Lorentzen
authors.forename: Erich
authors.initials: E
authors.lastname: Goldbach
authors.forename: George
authors.initials: G
authors.lastname: Tonn
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Sarah
authors.initials: S
authors.lastname: Wright
authors.forename: Kyle
authors.initials: K
authors.lastname: Powell
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
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; D001921:Brain / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006207:Half-Life; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009410:Nerve Degeneration / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D048031:JNK Mitogen-Activated Protein Kinases