title: Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2).
abstract: 3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (logD) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1mg/kg (po) in a pressure-overload model.
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 17-85, Jusohonmachi 2-chome, Osaka 532-8686, Japan. Asano_Yasutimi@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: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tamura
authors.forename: Manami
authors.initials: M
authors.lastname: Kaneko
authors.forename: Shota
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hideki
authors.initials: H
authors.lastname: Igata
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukumoto
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; 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: D000438:Alcohols; D000447:Aldehydes; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D048031:JNK Mitogen-Activated Protein Kinases; C039109:isoquinoline