Discovery of the Next Generation of Non-peptidomimetic Neurolysin Activators with High Blood-Brain Barrier Permeability: a Pharmacokinetics Study in Healthy and Stroke Animals.
Discovery of the Next Generation of Non-peptidomimetic Neurolysin Activators with High Blood-Brain Barrier Permeability: a Pharmacokinetics Study in Healthy and Stroke Animals.
复制标题
具有高血脑屏障渗透性的下一代非拟肽神经溶素激活剂的发现：健康和中风动物的药代动力学研究。
DOI：
10.1007/s11095-023-03619-5
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发表时间：
2023
影响因子：
3.7
通讯作者：
Abbruscato,ThomasJ
中科院分区：
文献类型：
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作者：
Zhang,Yong;Sharma,Sejal;Jonnalagadda,Shirisha;Kumari,Shikha;Queen,Aarfa;Esfahani,ShivaHadi;Archie,SabrinaRahman;Nozohouri,Saeideh;Patel,Dhavalkumar;Trippier,PaulC;Karamyan,VardanT;Abbruscato,ThomasJ
目的寻找神经溶解素（neurolysin，Nln）的药理学激活剂用于脑卒中治疗的研究日益受到关注。由于血脑屏障（BBB）的保护，中枢神经系统药物的发现仍然具有挑战性。先前报道的拟肽Nln激活剂显示出不令人满意的BBB渗透。在此，我们研究了下一代非拟肽Nln激活剂与高BBB permeability.MethodsA BBB模拟模型被用来评估他们的体外BBB通透性。进行蛋白结合、代谢稳定性和外排试验，以确定其未结合分数、血浆和脑中的半衰期以及BBB转运蛋白P-糖蛋白（P-gp）的依赖性。Thein vivopharmacokinetic配置文件在健康和中风mice.ResultsCompounds KS 52和KS 73出这一代表现出改善肽酶活性和血脑屏障通透性相比，内源性激活剂和以前的肽模拟物激活剂。它们显示出合理的血浆和脑蛋白结合，改善的代谢稳定性和P-gp介导的外排的独立性。在健康动物中，它们迅速分布到脑中，并在10 min时达到18.69%和12.10%注射剂量（ID）/ml的峰值水平。在4小时后，它们的总脑浓度仍然比它们的A50（增强50%肽酶活性所需的最小浓度）高7.78和12.34倍。此外，中风动物的同侧半球表现出相当的吸收相应的对侧半球和健康brain.ConclusionsThis研究提供了重要的细节的药代动力学特性的新一代的强有力的非拟肽NLN激活剂具有高血脑屏障通透性，并保证这些药物作为潜在的神经保护剂中风治疗的未来发展。
PurposeThere is growing interest in seeking pharmacological activation of neurolysin (Nln) for stroke treatment. Discovery of central nervous system drugs remains challenging due to the protection of the blood-brain barrier (BBB). The previously reported peptidomimetic Nln activators display unsatisfactory BBB penetration. Herein, we investigate the next generation of non-peptidomimetic Nln activators with high BBB permeability.MethodsA BBB-mimicking model was used to evaluate theirin vitroBBB permeability. Protein binding, metabolic stability, and efflux assays were performed to determine their unbound fraction, half-lives in plasma and brains, and dependence of BBB transporter P-glycoprotein (P-gp). Thein vivopharmacokinetic profiles were elucidated in healthy and stroke mice.ResultsCompounds KS52 and KS73 out of this generation exhibit improved peptidase activity and BBB permeability compared to the endogenous activator and previous peptidomimetic activators. They show reasonable plasma and brain protein binding, improved metabolic stability, and independence of P-gp-mediated efflux. In healthy animals, they rapidly distribute into brains and reach peak levels of 18.69% and 12.10% injected dose (ID)/ml at 10 min. After 4 h, their total brain concentrations remain 7.78 and 12.34 times higher than their A50(minimal concentration required for enhancing 50% peptidase activity). Moreover, the ipsilateral hemispheres of stroke animals show comparable uptake to the corresponding contralateral hemispheres and healthy brains.ConclusionsThis study provides essential details about the pharmacokinetic properties of a new generation of potent non-peptidomimetic Nln activators with high BBB permeability and warrants the future development of these agents as potential neuroprotective pharmaceutics for stroke treatment.