Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Rosana Leiva; Christian Griñan-Ferré; Constantí Seira; Elena Valverde; Andrew McBride; Margaret Binnie; Belén Pérez; F. Javier Luque; Mercè Pallàs; Axel Bidon-Chanal; Scott P. Webster; Santiago Vázquez

doi:10.1016/j.ejmech.2017.08.003

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Rosana Leiva, Christian Griñan-Ferré, Constantí Seira, Elena Valverde, Andrew McBride, Margaret Binnie, Belén Pérez, F. Javier Luque, Mercè Pallàs, Axel Bidon-Chanal, Scott P. Webster, Santiago Vázquez

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

Abstract

© 2017 Elsevier Masson SAS Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.

Original language	English
Pages (from-to)	412-428
Journal	European Journal of Medicinal Chemistry
Volume	139
DOIs	https://doi.org/10.1016/j.ejmech.2017.08.003
Publication status	Published - 20 Oct 2017

Keywords

11β-HSD1 inhibitors
Adamantane
Aged-related cognitive dysfunction
Alzheimer's disease
Drug design
Glucocorticoids
Polycyclic substituents
SAMP8 mouse

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Leiva, R., Griñan-Ferré, C., Seira, C., Valverde, E., McBride, A., Binnie, M., Pérez, B., Luque, F. J., Pallàs, M., Bidon-Chanal, A., Webster, S. P., & Vázquez, S. (2017). Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction. European Journal of Medicinal Chemistry, 139, 412-428. https://doi.org/10.1016/j.ejmech.2017.08.003

Leiva, Rosana ; Griñan-Ferré, Christian ; Seira, Constantí ; Valverde, Elena ; McBride, Andrew ; Binnie, Margaret ; Pérez, Belén ; Luque, F. Javier ; Pallàs, Mercè ; Bidon-Chanal, Axel ; Webster, Scott P. ; Vázquez, Santiago. / Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 139. pp. 412-428.

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title = "Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction",

abstract = "{\textcopyright} 2017 Elsevier Masson SAS Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.",

keywords = "11β-HSD1 inhibitors, Adamantane, Aged-related cognitive dysfunction, Alzheimer's disease, Drug design, Glucocorticoids, Polycyclic substituents, SAMP8 mouse",

author = "Rosana Leiva and Christian Gri{\~n}an-Ferr{\'e} and Constant{\'i} Seira and Elena Valverde and Andrew McBride and Margaret Binnie and Bel{\'e}n P{\'e}rez and Luque, {F. Javier} and Merc{\`e} Pall{\`a}s and Axel Bidon-Chanal and Webster, {Scott P.} and Santiago V{\'a}zquez",

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Leiva, R, Griñan-Ferré, C, Seira, C, Valverde, E, McBride, A, Binnie, M, Pérez, B, Luque, FJ, Pallàs, M, Bidon-Chanal, A, Webster, SP & Vázquez, S 2017, 'Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction', European Journal of Medicinal Chemistry, vol. 139, pp. 412-428. https://doi.org/10.1016/j.ejmech.2017.08.003

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction. / Leiva, Rosana; Griñan-Ferré, Christian; Seira, Constantí; Valverde, Elena; McBride, Andrew; Binnie, Margaret; Pérez, Belén; Luque, F. Javier; Pallàs, Mercè; Bidon-Chanal, Axel; Webster, Scott P.; Vázquez, Santiago.

In: European Journal of Medicinal Chemistry, Vol. 139, 20.10.2017, p. 412-428.

Research output: Contribution to journal › Article › Research › peer-review

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AU - Griñan-Ferré, Christian

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AU - Valverde, Elena

AU - McBride, Andrew

AU - Binnie, Margaret

AU - Pérez, Belén

AU - Luque, F. Javier

AU - Pallàs, Mercè

AU - Bidon-Chanal, Axel

AU - Webster, Scott P.

AU - Vázquez, Santiago

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KW - 11β-HSD1 inhibitors

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KW - Alzheimer's disease

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KW - Glucocorticoids

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