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Synthesis of new carnitine palmitoyltransferase I inhibitors derivatives of C75

Abstract:

Carnitine Palmitoyltransferase (CPT1) is an enzyme that catalyzes the transport of fatty acids from the cytosol into the mitochondria. CPT1 inhibition in the hypothalamus increases fatty acid levels, which produces an increased expression of anorexigenic neuropeptides, a sign of satiety. C75 acts as an antiobesity predrug. In vivo C75, is converted into C75-CoA adduct, which is a potent inhibitor of CPT1 and produces a loss of appetite and body weight. In this work, we present three new derivatives of C75, where the carboxylic group is replaced by a carnitine unit, malonic group, and a hydroxyl group with changes from trans to cis relative stereochemistry. Our results suggest that introducing a bigger group than carboxylic in β position or cis relative configuration of the lactone leads to a decrease of CPT1 inhibitory activity.