title: Synthesis and evaluation of a novel indoledione class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.
abstract: 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.
authors.affiliation: Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nagase
authors.forename: Takahide
authors.initials: T
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Nagumo
authors.forename: Ken
authors.initials: K
authors.lastname: Shimamura
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Kitazawa
authors.forename: Maki
authors.initials: M
authors.lastname: Kanesaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Katsumi
authors.initials: K
authors.lastname: Aragane
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: 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
chemical_list: C000630968:Elovl6 protein, mouse; D004791:Enzyme Inhibitors; D007211:Indoles; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases