Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2).
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.
Asano
Yasutomi
Y
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
Kitamura
Shuji
S
Ohra
Taiichi
T
Itoh
Fumio
F
Kajino
Masahiro
M
Tamura
Tomoko
T
Kaneko
Manami
M
Ikeda
Shota
S
Igata
Hideki
H
Kawamoto
Tomohiro
T
Sogabe
Satoshi
S
Matsumoto
Shin-ichi
S
Tanaka
Toshimasa
T
Yamaguchi
Masashi
M
Kimura
Hiroyuki
H
Fukumoto
Shoji
S
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
D000438:Alcohols; D000447:Aldehydes; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D048031:JNK Mitogen-Activated Protein Kinases; C039109:isoquinoline