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

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...