From Discovery and Translational Medicine, Intarcia Therapeutics, Inc., Research Triangle Park, North Carolina.
Anesthesiology. 2020 May;132(5):1229-1234. doi: 10.1097/ALN.0000000000003170.
Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure-activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.
设计、合成和药效评价超短效至长效阿片类镇痛药。作者：Feldman PL、James MK、Brackeen MF、Bilotta JM、Schuster SV、Lahey AP、Lutz MW、Johnson MR、Leighton HJ。《美国化学会志》1991 年；34:2202-8。版权所有 1991 年美国化学会。经许可重印。为了发现一种有效的超短效作用的μ阿片类镇痛药，它能够独立于肝功能代谢为无活性的物质，我们合成并评价了几类 4-苯胺基哌啶类镇痛药。有一类化合物表现出很强的μ阿片类激动剂活性，具有很高的镇痛效果和超短至长的作用持续时间。这些镇痛药，4-（甲氧羰基）-4-[1-氧代丙基）苯氨基]-1-哌啶基丙酸烷基酯，在豚鼠回肠中评估了它们的μ阿片类活性，在大鼠尾部退缩试验中评估了它们的镇痛效果和作用持续时间，在人全血中评估了它们在血液中的代谢能力。该系列化合物在体外均显示出很强的μ激动剂活性，但根据烷基酯取代基的不同，体内的效力和作用持续时间有很大差异。体外和体内活性之间的差异以及作用持续时间的变化可能是由于血液酯酶（s）对酯的水解速率不同所致。讨论了与镇痛活性和作用持续时间相关的[构效关系]，作为合成的各种酯的函数。还证明，超短效镇痛药 8 的作用持续时间不会因长时间输注或多次推注给药而改变。
