S 17092: A Prolyl Endopeptidase Inhibitor as a Potential Therapeutic Drug for Memory Impairment. Preclinical and Clinical Studies

Philippe Morain, Pierre Lestage, Guillaume De Nanteuil, Roeline Jochemsen, Jean-Loïc Robin, David Guez, Pierre-Alain Boyer
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引用次数: 98

Abstract

Any treatment that could positively modulate central neuropeptides levels would provide a promising therapeutic approach to the treatment of cognitive deficits associated with aging and/or neurodegenerative diseases. Therefore, based on the activity in rodents, S 17092 (2S,3aS,7aS)-1 ([(R.R)-2-phenylcyclopropyl]carbonyl)-2-[(thiazolidin-3-yl)car-bonyl]octahydro-1H-indole) has been selected as a potent inhibitor of cerebral prolyl-endopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short-term, long-term, reference and working memory in aged mice, as well as in rodents and monkeys with chemically induced amnesia or spontaneous memory deficits. S 17092 has also been safely administered to humans, and showed a clear peripheral expression of its mechanism of action through its inhibitory effect upon PEP activity in plasma. S 17092 exhibited central effects, as evidenced by EEG recording in healthy volunteers, and could improve a delayed verbal memory task. Collectively, the preclinical and clinical effects of S 17092 have suggested a promising role for this compound as an agent for the treatment of cognitive disorders associated with cerebral aging.

S 17092:一种脯氨酸内肽酶抑制剂作为治疗记忆障碍的潜在药物。临床前和临床研究
任何能够积极调节中枢神经肽水平的治疗方法都将为治疗与衰老和/或神经退行性疾病相关的认知缺陷提供一种有希望的治疗方法。因此,基于在啮齿动物体内的活性,我们选择s17092 (2S,3aS,7aS)-1 ([(R.R)-2-苯基环丙基]羰基)-2-[(噻唑烷-3-基)羰基]八氢- 1h -吲哚)作为脑脯氨酸内肽酶(PEP)的有效抑制剂。通过延缓神经活性肽的降解,s17092成功地用于各种记忆任务。这些任务探索了老年小鼠、啮齿类动物和猴子的短期、长期、参考和工作记忆,这些小鼠具有化学诱导的健忘症或自发性记忆缺陷。S 17092也已安全用于人体,并通过其对血浆PEP活性的抑制作用显示出其作用机制的明确外周表达。健康志愿者的脑电图记录证明,s17092表现出中枢效应,可以改善延迟的言语记忆任务。综上所述,s17092的临床前和临床效果表明,该化合物有望作为一种治疗脑衰老相关认知障碍的药物。
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