title: Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease.
abstract: A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Sánchez-Arias
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.affiliation: Anatomy Department, School of Medicine, University of Navarra , Irunlarrea 1, E-31008 Pamplona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.forename: Irene
authors.initials: I
authors.lastname: de Miguel
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-González
authors.forename: Ana
authors.initials: A
authors.lastname: Ugarte
authors.forename: Elena
authors.initials: E
authors.lastname: Sáez
authors.forename: Maria
authors.initials: M
authors.lastname: Espelosin
authors.forename: Susana
authors.initials: S
authors.lastname: Ursua
authors.affiliation: WuXi Apptec (Tianjin) Co. Ltd. , TEDA, No. 111 HuangHai Road, fourth Avenue, Tianjin 300456, PR China.
authors.forename: Tan
authors.initials: T
authors.lastname: Haizhong
authors.affiliation: WuXi Apptec (Tianjin) Co. Ltd. , TEDA, No. 111 HuangHai Road, fourth Avenue, Tianjin 300456, PR China.
authors.forename: Wu
authors.initials: W
authors.lastname: Wei
authors.affiliation: WuXi Apptec (Tianjin) Co. Ltd. , TEDA, No. 111 HuangHai Road, fourth Avenue, Tianjin 300456, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Musheng
authors.forename: Ana
authors.initials: A
authors.lastname: Garcia-Osta
authors.forename: Julen
authors.identifier: 0000-0003-1941-7255
authors.initials: J
authors.lastname: Oyarzabal
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002461:Cell Line, Transformed; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007963:Leukocytes, Mononuclear; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D000255:Adenosine Triphosphate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
keywords: Alzheimer’s disease; HDACs; PDE5; dual inhibitor; tadalafil; vardenafil