PDF(Pubmed)
Abstract：
All currently available general anesthetic agents possess potentially lethal side effects requiring their administration by highly trained clinicians. Among these agents is etomidate, a highly potent imidazole-based intravenous sedative-hypnotic that deleteriously suppresses the synthesis of adrenocortical steroids in a manner that is both potent and persistent. We developed two distinct strategies to design etomidate analogs that retain etomidate\'s potent hypnotic activity, but produce less adrenocortical suppression than etomidate. One strategy seeks to reduce binding to 11β-hydroxylase, a critical enzyme in the steroid biosynthetic pathway, which is potently inhibited by etomidate. The other strategy seeks to reduce the duration of adrenocortical suppression after etomidate administration by modifying the drug\'s structure to render it susceptible to rapid metabolism by esterases. In this chapter, we describe the methods used to evaluate the hypnotic and adrenocortical inhibitory potencies of two lead compounds designed using the aforementioned strategies. Our purpose is to provide a case study for the development of novel analogs of existing drugs with reduced side effects.
摘要：
所有目前可用的全身麻醉剂都具有潜在的致命副作用，需要训练有素的临床医生给药。这些药物中有依托咪酯，一种基于咪唑的高效静脉内镇静催眠药，以有效和持久的方式有害地抑制肾上腺皮质类固醇的合成。我们开发了两种不同的策略来设计保留依托咪酯有效催眠活性的依托咪酯类似物，但产生的肾上腺皮质抑制比依托咪酯少。一种策略旨在减少与11β-羟化酶的结合，类固醇生物合成途径中的关键酶，被依托咪酯有效抑制。另一种策略是通过改变药物的结构使其易于被酯酶快速代谢来减少依托咪酯给药后肾上腺皮质抑制的持续时间。在这一章中,我们描述了用于评估使用上述策略设计的两种先导化合物的催眠和肾上腺皮质抑制效力的方法.我们的目的是为开发具有减少副作用的现有药物的新型类似物提供案例研究。
