title: Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.
abstract: A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
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: Xiaochun
authors.initials: X
authors.lastname: Han
authors.forename: Tania
authors.initials: T
authors.lastname: Silva
authors.forename: Yun-Chou
authors.initials: YC
authors.lastname: Tan
authors.forename: Bindu
authors.initials: B
authors.lastname: Goyal
authors.forename: Parch
authors.initials: P
authors.lastname: Tivitmahaisoon
authors.forename: Alejandra
authors.initials: A
authors.lastname: Trejo
authors.forename: Wylie
authors.initials: W
authors.lastname: Palmer
authors.forename: Heather
authors.initials: H
authors.lastname: Hogg
authors.forename: Alam
authors.initials: A
authors.lastname: Jahagir
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Alam
authors.forename: Paul
authors.initials: P
authors.lastname: Wagner
authors.forename: Karin
authors.initials: K
authors.lastname: Stein
authors.forename: Lubov
authors.initials: L
authors.lastname: Filonova
authors.forename: Brad
authors.initials: B
authors.lastname: Loe
authors.forename: Ferenc
authors.initials: F
authors.lastname: Makra
authors.forename: David
authors.initials: D
authors.lastname: Rotstein
authors.forename: Lubica
authors.initials: L
authors.lastname: Rapatova
authors.forename: James
authors.initials: J
authors.lastname: Dunn
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: Johaness
authors.initials: J
authors.lastname: Hermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
mesh_terms: D018360:Crystallography, X-Ray; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048031:JNK Mitogen-Activated Protein Kinases