期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 150, 期 -, 页码 506-524出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.03.005
关键词
Dual inhibitors; PDE5 inhibition; HDAC6 selective; Alzheimer; Pharmacological tool compound; Tg2576 mice; In-vivo test
资金
- Foundation for Applied Medical Research (FIMA)
- University of Navarra (Pamplona, Spain)
- Asociacion de Amigos of University of Navarra
- Fundacion Fuentes Dutor
- Ministerio de Economia y Competitividad [FIS PI12/00710]
- Torres Quevedo subprogram [PTQ-14-07320]
- FIS projects [11/02861, 14/01244]
- Gobierno de Navarra [PI063]
We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo. (C) 2018 Elsevier Masson SAS. All rights reserved.
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