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. 2006 Jun 7;8(1):31–52. doi: 10.1111/j.1527-3458.2002.tb00214.x

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

Philippe Morain 1,✉, Pierre Lestage 1, Guillaume De Nanteuil 1, Roeline Jochemsen 1, Jean‐Loïc Robin 1, David Guez 1, Pierre‐Alain Boyer 1
PMCID: PMC6741683  PMID: 12070525

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.

Keywords: Memory enhancer, Prolyl endopeptidase inhibitor, S 17092, Cognitive disorders, Neuropeptides, Neuroprotection, Cerebral aging

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References

  • 1. Barelli H, Petit A, Hirsch E, et al. S 17092–1, a highly potent, specific and cell permeant inhibitor of human endopeptidase. Biochem Biophys Res Comm 1999;257:657–661. [DOI] [PubMed] [Google Scholar]
  • 2. Beal MF, Mazurek MF. Substance P‐like immunoreactivity is reduced in Alzheimer's disease cerebral cortex. Neurology 1987;37:1205–1209. [DOI] [PubMed] [Google Scholar]
  • 3. Bennett GW, Ballard TM, Watson CD, Fore KCF. Effects of neuropeptides on cognitive function. Exp Gerontol 1997;32:451–469. [DOI] [PubMed] [Google Scholar]
  • 4. Buck SH, Deshmukh PP, Burks TF, Yamamura HI. A survey of substance P, somastotatin, and neurotensin levels in aging in the rat and human central nervous system. Neurobiol Aging 1981;2:257–264. [DOI] [PubMed] [Google Scholar]
  • 5. Cohen NJ. Preserved learning capacity in amnesia: evidence for multiple sensory systems In: Squire LR, Butters N, Eds. Neuropsychology of memory. New York : Guilford Press, 1984:83–103. [Google Scholar]
  • 6. Cooper JA, Sagar HJ, Doherty SM, Jordan N, Tidswell P, Sullivan EV. Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson's disease. Brain 1992;115:1701–1725. [DOI] [PubMed] [Google Scholar]
  • 7. Dantzer R, Koob GF, Blithe R, Le Moal M. Septal vasopressin modulates social memory in male rats. Brain Res 1988;457:143. [DOI] [PubMed] [Google Scholar]
  • 8. Dekker A, Gispen WH, De Wied D. Axonal regeneration, growth factors and neuropeptides. Life Sci 1987;41:1667–1678. [DOI] [PubMed] [Google Scholar]
  • 9. Dupont A, Savard P, Merand Y, Labrie F, Boissier JR. Age‐related changes in central nervous system enke‐phalins and substance P. Life Sci 1998;29:2317–2322. [DOI] [PubMed] [Google Scholar]
  • 10. Ferrier IN, Cross AJ, Johnson JA, et al. Neuropeptides in Alzheimer type dementia. J Neurol Sci 1983;62:159–170. [DOI] [PubMed] [Google Scholar]
  • 11. Feuerstein TJ, Gleichauf O, Landwehrmeyer GB. Modulation of cortical acetylcholine release by serotonin: the role of substance P interneurons. Arch Pharmacol 1996;354:618. [DOI] [PubMed] [Google Scholar]
  • 12. Furtado JCS, Mazurek MF. Behavioral characterization of quinolinate‐induced lesions of the medial striatum: relevance for Huntington's disease. Exp Neurol 1996;138:158. [DOI] [PubMed] [Google Scholar]
  • 13. Giovannini MG, Casamenti F, Nistri A, Paoli F, Pepeu G. Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis. Br J Pharmacol 1991;102:363–368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Gotham AM, Brown RG, Marsden CD. Frontal” cognitive function in patients with Parkinson's disease “on” and “off levodopa. Brain 1988;111:299–321. [DOI] [PubMed] [Google Scholar]
  • 15. Hasenohrl RU, Huston JP, Schumman T. Neuropeptide Substance P improves water maze performance in aged rats. Psychopharmacol 1990;101:23–26. [DOI] [PubMed] [Google Scholar]
  • 16. Husain MM, Nemeroff CB. Neuropeptides and Alzheimer's disease. J Am Geriatr Soc 1990;38:9118–9125. [DOI] [PubMed] [Google Scholar]
  • 17. Huston JP, Hasenohrl RU. The role of neuropeptides in learning: focus on the neurokinin substance P. Behav. Brain Res 1995;66:117–127. [DOI] [PubMed] [Google Scholar]
  • 18. Iwasaki Y, Kinoshita M, Ikeda K, Takamiya K, Shiojima T. Trophic effect of various neuropeptides on the cultured ventral spinal cord of rat embryo. Neurosci Lett 1989;101:316–320. [DOI] [PubMed] [Google Scholar]
  • 19. Kanazawa I, Bird ED, O'Connell R, Powell D. Evidence for a decrease in substance P content of substantia nigra in Huntington's chorea. Brain Res 1977;119:447. [DOI] [PubMed] [Google Scholar]
  • 20. Katz RJ. Central injection of substance P elicits grooming behaviour and motor inhibition in mice. Neurosci Lett 1979;12:133. [DOI] [PubMed] [Google Scholar]
  • 21. Koida M, Walter R. Post‐proline cleaving enzyme. J Biol Chem 1976;251:75–93. [PubMed] [Google Scholar]
  • 22. Lange KW, Robbins TW, Marsden CD, James M, Owen AM, Paul GM. L‐dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacol 1992;107:394–404. [DOI] [PubMed] [Google Scholar]
  • 23. Lees AT, Smith E. Cognitive deficits in the early stages of Parkinson's disease. Brain 1983;106:257–270. [DOI] [PubMed] [Google Scholar]
  • 24. Lepagnol J, Lebrun C, Morain P, de Nanteuil G, Heider V. Cognition enhancing effects of S 17092, a potent and long acting inhibitor of post‐proline cleaving enzyme (PPCE). Soc Neurosci Abst 1996;142:111. [Google Scholar]
  • 25. Lestage P, Iris‐Hugot A, Gandon MH, Lepagnol J. Involvement of nicotinergic mechanisms in thyrotropin‐releasing hormone‐induced neurologic recovery after concussive head injury in the mouse. Eur J Pharmacol 1998;357:163–169. [DOI] [PubMed] [Google Scholar]
  • 26. Lestage P, Lebrun C, Iop F, et al. S 17092–1, a new post‐proline cleaving enzyme inhibitor: memory enhancing effects and substance P neuromodulatory activity. Adv Behav Biol 1998;49:653–660. [Google Scholar]
  • 27. Levin BE, Labre MM, Weiner WJ. Cognitive impairments associated with early Parkinson's disease. Neurology 1989;39:557–561. [DOI] [PubMed] [Google Scholar]
  • 28. Marighetto A, Etchamendy N, Touzani K, et al. Knowing which and knowing what: A potential mouse model for age‐related human declarative memory decline. Br J Neurosci 1999;11:3312–3322. [DOI] [PubMed] [Google Scholar]
  • 29. Mattioli R, Schwarting RKW, Huston JP. Recovery from unilateral 6‐hydroxydopamine lesion of substantia nigra promoted by the neurotachykinin substance P. Neuroscience 1992;48:595–605. [DOI] [PubMed] [Google Scholar]
  • 30. Mauborgne A, Javoy‐Agid F, Legrand JC, Agid Y, Cesselin F. Decrease in substance P‐like immunoreactivity in the substantia nigra and pallidum in Parkinsonian brains. Brain Res 1983;268:167–170. [DOI] [PubMed] [Google Scholar]
  • 31. Mc Donald RJ, White NM. A triple dissociation of memory systems: hippocampus, amygdala and dorsal striatum. Behav Neurosci 1993;107:3–22. [DOI] [PubMed] [Google Scholar]
  • 32. Mellow AH, Aronson SM, Giordani B, Berent S. A peptide enhancement strategy in Alzheimer's disease; Pilot study with TRH/physostigmine infusions. Biol Psychol 1993;34:271–273. [DOI] [PubMed] [Google Scholar]
  • 33. Mellow AH, Sunderland TS, Cohen RM, et al. Acute effects of high‐dose thyrotrophin‐releasing hormone infusions in Alzheimer's disease. Psychopharmacol 1989;98:403–407. [DOI] [PubMed] [Google Scholar]
  • 34. Molchan SE, Mellow AH, Hill JL, et al. The effects of thyrotrophin‐releasing hormone and scopolamine in Alzheimer's disease and normal volunteers. J Psychopharmacol 1992;6:489–500. [DOI] [PubMed] [Google Scholar]
  • 35. Molchan SE, Mellow AH, Lawlor BA, et al. TRH attenuates scopolamine‐induced memory impairment in humans. Psychopharmacol 1990;100:84–89. [DOI] [PubMed] [Google Scholar]
  • 36. Morain P, Robin JL, De Nanteuil G, Jochemsen R, Heidet V, Guez D. Pharmacodynamic and pharmaco‐kinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study. Br J Clin Pharmacol 2000;50:350–359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Owen AM, Beksinka M, James M, et al. Visuo‐spatial memory deficits at different stages of Parkinson's disease. Neuropsychologia 1993;31:627–644. [DOI] [PubMed] [Google Scholar]
  • 38. Owen AM, James M, Leigh PN, et al. Fronto‐striatal cognitive deficits at different stages of Parkinson's disease. Brain 1992;115:1727–1751. [DOI] [PubMed] [Google Scholar]
  • 39. Pitsikas N, Spruijt BM, Josephy M, Algeri S, Gispen WH. Effect of ORG 2766, an ACTH(4–9) analogue, on recovery after bilateral transection of the fimbria fornix in the rat. Pharmacol Biochem Behav 1991;38:931–934. [DOI] [PubMed] [Google Scholar]
  • 40. Portevin B, Benoist A, Remond G, et al. New prolyl endopeptidase inhibitors: in vitro and in vivo activities of azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane, and perhytroindole derivatives. J med Chem 1996;39:2379–2391. [DOI] [PubMed] [Google Scholar]
  • 41. Quigley BI, Kowall NW. Substance P‐like immunoreactive neurons are depleted in Alzheimer's disease cerebral cortex. Neuroscience 1991;41:41. [DOI] [PubMed] [Google Scholar]
  • 42. Rossor MN, Emson PC, Dawbam D, Mountjoy CQ, Roth M. Neuropeptide and dementia. Progr Brain Res 1986;66:143–159. [PubMed] [Google Scholar]
  • 43. Schneider JS, Giardiniere M, Morain P. Effects of the prolyl endopeptidase inhibitor S 17092 on cognitive deficits in chronic low dose MPTP‐treated monkeys. Neuropsychopharmacology 2002;26:176–182. [DOI] [PubMed] [Google Scholar]
  • 44. Schneider JS, Kovelowski CJ. Chronic exposure to low doses of MPTP. I. Cognitive deficits in motor asymptomatic monkeys. Brain Res 1990;519:122–128. [DOI] [PubMed] [Google Scholar]
  • 45. Schneider JS, Roeltgen DP. Delayed matching‐to‐sample, object retrieval, and discrimination reversal deficits in chronic low dose MPTP‐treated monkeys. Brain Res 1993;615:351–354. [DOI] [PubMed] [Google Scholar]
  • 46. Stanfield PR, Nakajima Y, Yamaguchi K. Substance P raises neuronal membrane excitability by reducing inward rectification. Nature 1985;315:498. [DOI] [PubMed] [Google Scholar]
  • 47. Stoessl AJ, Szczutkowski C, Glenn B, Watson I. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions. Brain Res 1991;565:254. [DOI] [PubMed] [Google Scholar]
  • 48. Tenovuo O, Kolhinen O, Laihinen A, Rinne UX. Brain substance P receptors in Parkinson's disease In: Advances in Neurology, Vol. 53, Parkinson's Disease: Anatomy, Pathology, and Therapy, Streifler MB, Korczyn AD, Melamed E, Youdim MBH, Eds. New York : Raven Press, 1990;145–148. [PubMed] [Google Scholar]
  • 49. Van Wimersma Greidanus TB, Maigret C. Grooming behaviour induced by substance P. Eur J Pharmacol 1988;15:217. [DOI] [PubMed] [Google Scholar]
  • 50. Wang ZP, Man SY, Tang F. Age‐related changes in the contents of neuropeptides in the brain and pituitary. Neurobiol Aging 1981;15:529–534. [DOI] [PubMed] [Google Scholar]
  • 51. Whitty CJ, Kapatos G, Bannon MJ. Neurotrophic effects of substance P on hippocampal neurons in vitro. Neurosci Lett 1993;164:141–144. [DOI] [PubMed] [Google Scholar]
  • 52. Wilk S. Minireview on prolyl endopeptidase. Life Sci 1983;33:2149–2157. [DOI] [PubMed] [Google Scholar]
  • 53. Winkler J, Suhr ST, Gage FH, Thal LI, Fisher LJ. Essential role of neocortical acetylcholine in spatial memory. Nature 1995;375:484. [DOI] [PubMed] [Google Scholar]

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