Synthesis and evaluation of a novel indoledione class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.
Novel indoledione derivatives were synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Systematic optimization of an indole class of lead 1 led to the identification of potent ELOVL6 selective inhibitors. Representative inhibitor 37 showed sustained plasma exposure and good liver penetrability in mice. After oral administration, 37 potently inhibited ELOVL6 activity in the liver in mice.
Takahashi
Toshiyuki
T
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Nagase
Tsuyoshi
T
Sasaki
Takahide
T
Nagumo
Akira
A
Shimamura
Ken
K
Miyamoto
Yasuhisa
Y
Kitazawa
Hidefumi
H
Kanesaka
Maki
M
Yoshimoto
Ryo
R
Aragane
Katsumi
K
Tokita
Shigeru
S
Sato
Nagaaki
N
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000081031:Fatty Acid Elongases; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D013329:Structure-Activity Relationship
C000630968:Elovl6 protein, mouse; D004791:Enzyme Inhibitors; D007211:Indoles; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases