The selective inhibition of individual carnitine acyltransferases may be useful in the therapy of diabetes and heart disease. Aminocarnitine (3) is a weak competitive inhibitor (K(i) = 4.0 mM) for carnitine acetyltransferase (CAT), although the N-acetyl derivative 4 is about 165 times more potent (K(i) = 0.024 mM) than 3. Compound 3 is also a potent competitive inhibitor for carnitine palmitoyltransferases 1 and 2 (CPT-1 and CPT-2) (IC50 for CPT-2 = 805 nM). We synthesized 3-amino-5,5-dimethylhexanoic acid (7) and its N-acetyl derivative (8) as isosteric analogs of 3 and 4 that lack the quaternary ammonium positive charge. Like 3 and 4, compounds 7 and 8 were competitive inhibitors of CAT with significantly different potencies, but in this case, 8 (K(i) = 25 mM) was 10 times less potent than 7 (K(i) = 2.5 mM). R-(-)-7 and S-(+)-7 were stereoselective inhibitors of CAT (K(i) = 1.9 and 9.2 mM, respectively). Racemic 7 was a weak competitive inhibitor of CPT-2 (K(i) = 20 mM) and had no effect on CPT-1. These results are consistent with differences among the carnitine-binding sites on carnitine acyl-transferases that may be useful in selective inhibitor design. Furthermore, the data suggest that the quaternary ammonium positive charge of carnitine may be important for the proper orientation of carnitine and its analogs in the binding site.

中文翻译：

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3-氨基-5,5-二甲基己酸。合成，拆分和对肉碱酰基转移酶的影响。

个别肉碱酰基转移酶的选择性抑制可用于治疗糖尿病和心脏病。氨基肉碱（3）是肉碱乙酰基转移酶（CAT）的弱竞争抑制剂（K（i）= 4.0 mM），尽管N-乙酰基衍生物4的效力（K（i）= 0.024 mM）比3约强165倍。化合物3还是肉碱棕榈酰转移酶1和2（CPT-1和CPT-2）的有效竞争抑制剂（CPT-2的IC50 = 805 nM）。我们合成了3-氨基-5,5-二甲基己酸（7）及其N-乙酰基衍生物（8），作为缺少季铵正电荷的3和4的等排类似物。像3和4一样，化合物7和8是竞争性的CAT CAT，其效价差异很大，但在这种情况下，8（K（i）= 25 mM）的效力是7（K（i）= 2.5 mM）的10倍。R-（-）-7和S-（+）-7是CAT的立体选择性抑制剂（K（i）分别为1.9和9.2 mM）。外消旋体7是CPT-2的弱竞争抑制剂（K（i）= 20 mM），对CPT-1没有影响。这些结果与肉碱酰基转移酶上肉碱结合位点之间的差异一致，这在选择性抑制剂设计中可能有用。此外，数据表明肉碱的季铵正电荷可能对肉碱及其类似物在结合位点的正确取向很重要。