Potent biphenyl- and 3-phenyl pyridine-based inhibitors of acetyl-CoA carboxylase.
We report the synthesis and enzymatic evaluation of potent inhibitors of acetyl-CoA carboxylases (ACCs) containing biphenyl or 3-phenyl pyridine cores. These compounds inhibit both ACC1 and ACC2, or are moderately selective for either enzyme, depending on side chain substitution. Typical activities of the most potent compounds in this class are in the low double-digit to single-digit nanomolar range in in vitro assays using human ACC1 and ACC2 enzymes.
Haque
Tasir S
TS
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. tasir.haque@bms.com
Liang
Ningning
N
Golla
Rajasree
R
Seethala
Ramakrishna
R
Ma
Zhengping
Z
Ewing
William R
WR
Cooper
Christopher B
CB
Pelleymounter
Mary Ann
MA
Poss
Michael A
MA
Cheng
Dong
D
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase