1. Academic Validation
  2. Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors

Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors

  • ACS Chem Neurosci. 2019 Mar 20;10(3):1765-1782. doi: 10.1021/acschemneuro.8b00648.
Obdulia Rabal Juan A Sánchez-Arias Mar Cuadrado-Tejedor 1 Irene de Miguel Marta Pérez-González Carolina García-Barroso Ana Ugarte Ander Estella-Hermoso de Mendoza Elena Sáez Maria Espelosin Susana Ursua Tan Haizhong 2 Wu Wei 2 Xu Musheng 2 Ana Garcia-Osta Julen Oyarzabal
Affiliations

Affiliations

  • 1 Anatomy Department, School of Medicine , University of Navarra , Irunlarrea 1 , E-31008 Pamplona , Spain.
  • 2 WuXi Apptec (Tianjin) Co. Ltd. , TEDA, No. 111 HuangHai Road, Fourth Avenue , Tianjin 300456 , PR China.
Abstract

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the Other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).

Keywords

Alzheimer’s disease; PDE5 inhibition; chemical probes; class I HDAC selective inhibition; dual inhibitors; in vivo test.

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