Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
Expert Opin Ther Pat. 2011 Aug;21(8):1159-71. doi: 10.1517/13543776.2011.586339. Epub 2011 May 24.
Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis.
This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors.
The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties and potential uses of such agents are discussed here.
羧酸酯酶在许多治疗活性化合物的水解中起着重要作用。这在一定程度上是由于酯基在这些小分子中的普遍存在。然而，在分子开发之前，很少有人考虑这些酶可能对药物稳定性和药代动力学产生的影响。因此，该类蛋白质的选择性抑制剂的应用可能在调节药物代谢、分布和毒性方面具有实用价值，这些药物易受到酶水解的影响。
本综述详细介绍了自 1986 年以来所有此类化合物的发展情况，但主要集中在最近确定的选择性人羧酸酯酶抑制剂上。
羧酸酯酶抑制剂的应用可能会极大地推动药物发现的发展。这些分子可以提高被这类酶失活的化合物的疗效，或者降低被这些蛋白质激活的药物的毒性。此外，由于缺乏羧酸酯酶活性似乎没有明显的生物学后果，这些化合物可以与几乎任何酯化药物联合使用。因此，这些蛋白质的抑制剂可能在改变药物在体内的水解和分布方面具有实用价值。本文讨论了这些药物的特点、化学和生物学特性以及潜在用途。
