Scientific publications

Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease

Apr 25, 2018 | Magazine: European Journal of Medicinal Chemistry

Obdulia Rabal, Juan A Sánchez-Arias, Mar Cuadrado-Tejedor, Irene de Miguel, Marta Pérez-González, Carolina García-Barroso, Ana Ugarte, Ander Estella-Hermoso de Mendoza, Elena Sáez, Maria Espelosin, Susana Ursua, Tan Haizhong, Wu Wei, Xu Musheng, Ana Garcia-Osta, Julen Oyarzabal


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.

CITATION  Eur J Med Chem. 2018 Apr 25;150:506-524. doi: 10.1016/j.ejmech.2018.03.005. Epub 2018 Mar 20.

Our authors

Dr. Mar Cuadrado Tejedor
Elena Sáez de Blas
Laboratory technician Medicinal Chemistry Research Group
María Espelosín Azpilicueta
Susana Ursúa Santos
Laboratory technician Epilepsy Research Group