Synthesis and Evaluation of a Novel Indoledione Class of Long Chain Fatty Acid Elongase 6 (ELOVL6) Inhibitors

• Published in: Journal of medicinal chemistry Vol. 52; no. 10; pp. 3142 - 3145
• Main Authors: Takahashi, Toshiyuki, Nagase, Tsuyoshi, Sasaki, Takahide, Nagumo, Akira, Shimamura, Ken, Miyamoto, Yasuhisa, Kitazawa, Hidefumi, Kanesaka, Maki, Yoshimoto, Ryo, Aragane, Katsumi, Tokita, Shigeru, Sato, Nagaaki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.05.2009; Amer Chemical Soc
• Subjects: Acetyltransferases - antagonists & inhibitors; Administration, Oral; Animals; Biological and medical sciences; Chemistry, Medicinal; Drug Stability; Enzyme Inhibitors - blood; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Indoles - chemical synthesis; Indoles - pharmacology; Life Sciences & Biomedicine; Liver - metabolism; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; GENE FAMILY; METABOLISM; IDENTIFICATION; CLONING; ADIPOSE-TISSUE; Human; Acyltransferases; Enzyme; Nitrogen heterocycle; Transferases; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Selectivity; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Bicyclic compound; Fluorine Organic compounds; Pharmacokinetics; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900391x

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.