Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer’s Disease

Abstract

Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

“…The newly established memories were firmly sustained over a 2-week period in HDACi-treated transgenic AD mice (Kilgore et al, 2010). Recently, inhibition of phosphodiesterase 5 (PDE5) and HDAC has been suggested as a potent novel therapeutic approach for AD (Rabal et al, 2016;Sá nchez-Arias et al, 2017;Rabal et al, 2018). An acridine-based HDAC inhbitor, designed as a multi-target agent against HDAC and acetylcholine esterase showed selective inhbition of HDAC6 and strong activity against Ab-aggregation (Tseng et al, 2020).…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…into one molecule, to take advantage of the presence of large hydrophobic patches at the HDAC surface rim . Some encouraging results have been reported (Figure ), such as dual‐acting HDAC and topoisomerase II inhibitor 135 , triple HDAC and topoisomerase I/II inhibitor 136 , photoactivatable platinum(IV) complex cis , trans ‐[Pt(N 3 ) 2 (Sub) 2 (tBu 2 bpy)] ( 137 ) targeting genomic DNA and HDAC, dual‐acting estrogen receptor and HDAC inhibitor 138 , tamoxifen‐HDACI conjugate 139 and ethynyl‐estradiol‐HDACi conjugate 140 , chimeric 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGR)‐HDAC inhibitor 141 , dual‐acting androgen receptor (AR) and HDAC inhibitor 142 , stilbene‐SAHA chimeric molecule 143 , nitric oxide (NO)‐donor HDAC inhibitor 144 , chimeric c‐Src kinase and HDAC inhibitor 145 , and dual‐acting phosphodiesterase 5 (PDE5) and HDACs inhibitors 146 and 147 , JAK2‐HDAC dual inhibitor 148 (EY3238), JAK1‐HDAC dual inhibitor 149 , JAK2‐HDAC6 dual inhibitor 150 , PI3K‐HDAC dual inhibitors 151 , 152 , LSD1‐HDAC dual inhibitor 153 (Corin), IDO1‐HDAC dual inhibitor 154 and NAMPT‐HDAC dual inhibitor 155 , mammalian target of rapamycin‐HDAC dual inhibitor 156 . The design rationale for MTDLs is underpinned by deep insights derived from structural bioinformatics and structural biology.…”

Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death

“…Therefore, we wondered whether it might be of any advantage to design a class of multiple ligands (ML) able to modulate both targets instead of using different inhibitors. HDACi‐based MLs have found massive application in the field of anticancer drug discovery, while only recently Oyarzabal and co‐workers reported the first HDAC–phosphodiesterase dual inhibitors as neuroprotective agents …”

“…HDACi-based MLs have found massive application in the field of anticancer drug discovery,w hile only recently Oyarzabal and co-workers reported the first HDAC-phosphodiesterase dual inhibitors as neuroprotective agents. [15] Concerning TG2 inhibitors, only af ew classes of inhibitors have been discovered; [16] among them,o fp articular note are the 3-(substituted cinnamoyl)pyridines, such as compound 1 (Figure 2). [17] By analyzing the structure-activity relationships of this series of compounds, it turned out that the para position of the cinnamoylp henyl ring could be substituted with bulky groups withoutd ecrease in the inhibitory potency.N otably,t o the best of our knowledge,T G2 inhibitors have never been used before to design MLs.…”