Synthesis and biological evaluation of a novel 3-sulfonyl-8-azabicyclo[3.2.1]octane class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.
Long chain fatty acid elongase 6 (ELOVL6) catalyzes the elongation of long chain fatty acyl-CoAs and is a potential target for the treatment of metabolic disorders. The ultrahigh throughput screen of our corporate chemical collections resulted in the identification of a novel 3-sulfonyl-8-azabicyclo[3.2.1]octane class of ELOVL6 inhibitor 1a. Optimization of lead 1a led to the identification of the potent, selective, and orally available ELOVL6 inhibitor 1w.
Nagase
Tsuyoshi
T
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki 300-2611, Japan. tsnagase@gmail.com
Takahashi
Toshiyuki
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*; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000081031:Fatty Acid Elongases; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009795:Octanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; D004791:Enzyme Inhibitors; D009795:Octanes; D013450:Sulfones; D014326:Tropanes; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases