Agonism of the endothelial receptor APJ (putative receptor protein related to AT₁; AT₁: angiotensin II receptor type 1) has the potential to ameliorate congestive heart failure by increasing cardiac output without inducing hypertrophy. Although the endogenous agonist, pyr-apelin-13 (1), has shown beneficial APJ-mediated inotropic effects in rats and humans, such effects are short-lived given its extremely short half-life. Here, we report the conjugation of 1 to a fatty acid, providing a lipidated peptide (2) with increased stability that retains inotropic activity in an anesthetized rat myocardial infarction (MI) model. We also report the preparation of a library of 15-mer APJ agonist peptide-lipid conjugates, including adipoyl-γGlu-OEG-OEG-hArg-r-Q-hArg-P-r-NMeLeu-S-H-K-G-Oic-pIPhe-P-DBip-OH (17), a potent APJ agonist with high plasma protein binding and a half-life suitable for once-daily subcutaneous dosing in rats. A correlation between subcutaneous absorption rate and lipid length/type of these conjugates is also reported

内皮受体APJ（与AT ₁有关的假定受体蛋白； AT ₁：血管紧张素II受体1型）的激动作用有可能通过增加心输出量而不引起肥大来改善充血性心力衰竭。尽管内源性激动剂pyr-apelin-13（1）在大鼠和人类中显示出有益的APJ介导的正性肌力作用，但鉴于其半衰期极短，这种作用是短暂的。在这里，我们报告1与脂肪酸的结合，提供了脂化的肽（2）具有更高的稳定性，在麻醉的大鼠心肌梗死（MI）模型中保持正性肌力活动。我们还报告了15-mer APJ激动剂肽-脂质缀合物文库的制备，包括己二酰基-γGlu-OEG-OEG-hArg-rQ-hArg-Pr-NMeLeu-SHKG-Oic-pIPhe-P-DBip-OH（17），一种有效的APJ激动剂，具有高血浆蛋白结合力和半衰期，适用于大鼠每天一次皮下给药。还报道了这些缀合物的皮下吸收率和脂质长度/类型之间的相关性。