title: Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1).
abstract: A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed.
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 17-85, Jusohonmachi 2-chome, Osaka 532-8686, Japan. Asano_Yasutomi@takeda.co.jp
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Asano
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitamura
authors.forename: Taiichi
authors.initials: T
authors.lastname: Ohra
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Aso
authors.forename: Hideki
authors.initials: H
authors.lastname: Igata
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tamura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D048031:JNK Mitogen-Activated Protein Kinases; C039109:isoquinoline