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

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Abstract / Description of output

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
Number of pages	17
Journal	European Journal of Medicinal Chemistry
Volume	139
Early online date	4 Aug 2017
DOIs	https://doi.org/10.1016/j.ejmech.2017.08.003
Publication status	E-pub ahead of print - 4 Aug 2017

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Journal Article

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10.1016/j.ejmech.2017.08.003

1-s2.0-S0223523417306062-mainAccepted author manuscript, 1.73 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

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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. Advance online publication. https://doi.org/10.1016/j.ejmech.2017.08.003

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

abstract = "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.",

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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

TY - JOUR

T1 - Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

AU - Leiva, Rosana

AU - Griñan-Ferré, Christian

AU - Seira, Constantí

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

PY - 2017/8/4

Y1 - 2017/8/4

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.ejmech.2017.08.003

DO - 10.1016/j.ejmech.2017.08.003

M3 - Article

C2 - 28818766

SN - 0223-5234

VL - 139

SP - 412

EP - 428

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

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