Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1).
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.
Asano
Yasutomi
Y
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
Kitamura
Shuji
S
Ohra
Taiichi
T
Aso
Kazuyoshi
K
Igata
Hideki
H
Tamura
Tomoko
T
Kawamoto
Tomohiro
T
Tanaka
Toshimasa
T
Sogabe
Satoshi
S
Matsumoto
Shin-ichi
S
Yamaguchi
Masashi
M
Kimura
Hiroyuki
H
Itoh
Fumio
F
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
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D048031:JNK Mitogen-Activated Protein Kinases; C039109:isoquinoline