Etomidate Analogues as Safer General Anesthetics

描述（由申请人提供）：仅在美国，每年就有近3000万例全身麻醉剂被使用。在产生麻醉所需的剂量下，所有的全身麻醉剂都会产生严重的副作用。心血管和呼吸功能的抑制是最值得关注的，特别是在危重患者中。这种抑郁解释了为什么麻醉剂的治疗指数是所有药物中最低的。本研究的重点是依托咪酯，它与其他全身麻醉药不同，具有良好的血液动力学和呼吸作用，治疗指数异常高。然而，由于依托咪酯能有效抑制112-羟化酶，导致肾上腺皮质类固醇合成的长期抑制，可能导致致命的后果，因此其临床应用有效地限制在危重患者中，只能单次给药诱导麻醉。这项工作的广泛、长期目标是为开发保留依托咪酯有益特性的新型麻醉剂提供基础，但其对类固醇合成的影响大大降低。这将扩大临床应用范围，使其超越丸给药，包括持续输注麻醉维持和可能的长期镇静。拟议的研究将定义新型依托咪酯类似物的结构-活性关系，并测试开发依托咪酯类似物的两种新策略，这些类似物可以持续输注，因为它们抑制肾上腺皮质功能的能力在持续时间或程度上显着降低。第一种策略是设计依托咪酯类似物，这种类似物代谢非常迅速，在手术结束时停止输注，而不是在手术后持续几天，肾上腺皮质功能的抑制就会终止。这类药物也有望在麻醉后产生更快、更可预测的苏醒。第二种策略是设计麻醉剂依托咪酯类似物，不与112-羟化酶高亲和力结合，因此在临床相关剂量下不会抑制类固醇合成。具体目的1是确定新的代谢不稳定的依托咪酯类似物（依托咪酯）及其羧酸代谢物的体外结构-活性关系。具体目的2是在大鼠模型中确定连续输注依托咪酯是否会抑制肾上腺皮质、心血管或呼吸功能，如果有，将这种抑制与连续输注依托咪酯产生的抑制进行比较。具体目标3是定位和表征人112-羟化酶上依托咪酯结合位点，并定义与112-羟化酶血红素铁协调能力不同的新型依托咪酯类似物的结构-活性关系。

DESCRIPTION (provided by applicant): In the U.S. alone, nearly 30 million general anesthetics are administered each year. At the doses required to produce anesthesia, all general anesthetics produce serious side effects. Depression of cardiovascular and respiratory function is of greatest concern, particularly in the critically ill. Such depression explains why anesthetics have among the lowest therapeutic indices of any class of drugs. This proposal focuses on etomidate, which is distinguished from other general anesthetics by its favorable hemodynamic and respiratory effects and its unusually high therapeutic index. However because etomidate potently inhibits 112- hydroxylase, leading to prolonged suppression of adrenocortical steroid synthesis with potentially fatal consequences, its clinical use is effectively limited in the critically ill to single bolus administration for the induction of anesthesia. The broad, long-term goal of this work is to provide the groundwork for the development of novel anesthetics that retain etomidate's beneficial properties, but whose impact on steroid synthesis is greatly reduced. This would extend clinical utility beyond bolus administration to include continuous infusion for anesthetic maintenance and possibly long-term sedation. The proposed studies will define structure-activity relationships for novel etomidate analogues and test new two strategies for developing analogues of etomidate that can be continuously infused because their abilities to inhibit adrenocortical function are significantly reduced in duration or magnitude. The first strategy is to design etomidate analogues that are so rapidly metabolized that suppression of adrenocortical function terminates when their infusion is stopped at the end of surgery rather than persisting for days afterward. Such agents are also expected to produce more rapid and predictable emergence from anesthesia. The second strategy is to design anesthetic etomidate analogues that do not bind to 112-hydroxylase with high affinity and, therefore, do not inhibit steroid synthesis at clinically relevant doses. Specific Aim 1 is to define in vitro structure-activity relationships for novel metabolically-labile etomidate analogues (etomidate esters) and their carboxylic acid metabolites. Specific Aim 2 is to determine in a rat model whether continuous infusions of etomidate esters depress adrenocortical, cardiovascular, or respiratory function and if so, to compare such depression to that produced by continuous infusions of etomidate. Specific Aim 3 is to locate and characterize the etomidate binding site(s) on human 112-hydroxylase and to define structure-activity relationships for novel etomidate analogues whose abilities to coordinate with 112-hydroxylase's heme iron vary. PUBLIC HEALTH RELEVANCE: There is a great need for safer general anesthetics, particularly for use in critically ill patients. Etomidate possesses many properties that make it an ideal anesthetic agent, but because it produces prolonged and potentially deadly suppression of adrenocortical function, its clinical utility is limited in the critically ill to single bolus administration for the induction of anesthesia. The proposed studies will define structure-activity relationships and test two novel strategies (one pharmacokinetic and the other pharmacodynamic) for developing analogues of etomidate that retain etomidate's beneficial properties, but may be safely administered by continuous infusion to maintain anesthesia because their abilities to suppress adrenocortical function are reduced in duration or magnitude. The successful application of one or both of these strategies to develop novel etomidate analogues will improve human health by permitting anesthesia to be administered more safely to patients who are at greatest risk: the critically ill.