Etomidate Analogues as Safer General Anesthetics

描述(申请人提供)：仅在美国，每年就有近3000万种全身麻醉药被使用。在产生麻醉所需的剂量下，所有全身麻醉药都会产生严重的副作用。心血管和呼吸功能的抑制是最令人担忧的，尤其是在危重病人中。这种抑郁解释了为什么麻醉药的治疗指数是所有药物中最低的。这项建议侧重于依托咪酯，它与其他全身麻醉药不同的是，它具有良好的血流动力学和呼吸作用，而且治疗指数非常高。然而，由于依托咪酯有效地抑制112-羟基酶，导致肾上腺皮质类固醇合成的长期抑制，从而导致潜在的致命后果，其临床应用有效地限制在危重病人中，仅限于单次给药以诱导麻醉。这项工作的广泛和长期目标是为开发新的麻醉药奠定基础，这些麻醉药保留依托咪酯的有益特性，但其对类固醇合成的影响大大降低。这将扩大临床用途，超越团注给药，包括用于麻醉维持和可能的长期镇静的持续输液。拟议的研究将确定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，这些类似物可以连续输注，因为它们抑制肾上腺皮质功能的能力在持续时间或幅度上显著降低。第一种策略是设计代谢如此迅速的依托咪酯类似物，当它们在手术结束时停止输注时，肾上腺皮质功能的抑制就会终止，而不是在手术后持续数天。这类药物还有望更快、更可预测地从麻醉中苏醒过来。第二种策略是设计麻醉剂依托咪酯类似物，不与112-羟基酶高亲和力结合，因此在临床相关剂量下不抑制类固醇合成。具体目标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是确定在大鼠模型中持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，如果是的话，将这种抑制与持续输注依托咪酯所产生的抑制进行比较。具体目标3是定位和表征人112-羟基酶上依托咪酯结合位点(S)，并确定与112-羟基酶的血红素铁配位能力不同的新依托咪酯类似物的构效关系。 公共卫生相关性：非常需要更安全的全身麻醉药，特别是用于危重患者的麻醉药。依托咪酯具有许多特性，使其成为一种理想的麻醉剂，但由于它对肾上腺皮质功能产生长期的、潜在的致命抑制，其临床应用在危重病人中受到限制，仅限于单次给药以诱导麻醉。拟议的研究将确定结构-活性关系，并测试两种开发依托咪酯类似物的新策略(一种是药动学，另一种是药效学)，这些策略保留了依托咪酯的有益性质，但可以通过持续输注来安全地维持麻醉，因为它们抑制肾上腺皮质功能的能力在持续时间或幅度上都有所降低。成功地应用这两种策略中的一种或两种来开发新型依托咪酯类似物，将使麻醉更安全地应用于风险最高的患者：危重患者，从而改善人类健康。

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.