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The syntheses of (R)- and (S)-norcarnitine ethyl esters are described starting with an optimized, chiral chemical reduction of ethyl 4-chloroacetoacetate followed by azide substitution, reduction, and dimethylation. The reaction of (R)- and (S)-norcarnitine ethyl esters with 1-bromoheptadecan-2-one gives ()- and (-)-6-[(methoxycarbonyl)methyl]-2- pentadecyl-4,4-dimethylmorpholinium bromide, respectively, which hydrolyzes to ()- and (-)-6-(carboxylatomethyl)-2- pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, ()- and (-)-HPC), respectively, upon treatment with a hydroxide resin. ()- and (-)-HPC are reversible active-site directed inhibitors of hepatic mitochondrial CPTs. Both stereoisomers inhibit CPT I and CPT II in control and streptozotocin diabetic rat to the same extent (Imax = 100). Using intact mitochondria (CPT I), I50 values for (-)-HPC and ()-HPC were 15.5 M and 47.5 M, respectively. The I50 values for CPT II were 6.7 M and 38.5 M for (-)-HPC and ()-HPC, respectively. The mode of inhibition was uncompetitive for CPT I with respect to acyl-CoA. The apparent Ki for (-)-HPC is about 5 M. These data suggest that (-)-HPC may be useful for further evaluation as an antidiabetic agent.

The syntheses of (R)- and (S)-norcarnitine ethyl esters are described starting with an optimized, chiral chemical reduction of ethyl 4-chloroacetoacetate followed by azide substitution, reduction, and dimethylation. The reaction of (R)- and (S)-norcarnitine ethyl esters with 1-bromoheptadecan-2-one gives (+)- and (-)-6-[(methoxycarbonyl)methyl]-2- pentadecyl-4,4-dimethylmorpholinium bromide, respectively, which hydrolyzes to (+)- and (-)-6-(carboxylatomethyl)-2- pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, (+)- and (-)-HPC), respectively, upon treatment with a hydroxide resin. (+)- and (-)-HPC are reversible active-site directed inhibitors of hepatic mitochondrial CPTs. Both stereoisomers inhibit CPT I and CPT II in control and streptozotocin diabetic rat to the same extent (Imax = 100%). Using intact mitochondria (CPT I), I50 values for (-)-HPC and (+)-HPC were 15.5 μM and 47.5 μM, respectively. The I50 values for CPT II were 6.7 μM and 38.5 μM for (-)-HPC and (+)-HPC, respectively. The mode of inhibition was uncompetitive for CPT I with respect to acyl-CoA. The apparent Ki for (-)-HPC is about 5 μM. These data suggest that (-)-HPC may be useful for further evaluation as an antidiabetic agent.