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Description

A cell-permeable, spiral ketone derivative that acts as a highly potent inhibitor of acetyl-CoA carboxylase (ACC, IC50 = 27 and 33 nM for human ACC1 and ACC2, respectively). The inhibition appears to be uncompetitive with respect to ATP and non-competitive with carbonate and acetyl-CoA. Inhibits malonyl-CoA synthesis in primary rat hepatocytes (IC50 = 29.9 nM) and reduces de novo hepatic lipid synthesis (ED50 = 7.8 mg/kg in rats). Acutely reduces whole body respiratory exchange ratio (RER) to indicate a switch to fatty acid utilization. Has low protein binding in rat and dog plasma, but exhibits about 10-fold higher binding in monkey and human plasma. Displays favorable pharmacokinetic properties with good bioavailability, microsomal stability, and low plasma clearance (t1/2 = 4.8 h in rat and 5.7 h in dog, at 3 mg/kg, p.o.).