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.
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 ).
Obdulia
O
Rabal
Juan A
JA
Sánchez-Arias
Anatomy Department, School of Medicine, University of Navarra , Irunlarrea 1, E-31008 Pamplona, Spain.
Mar
M
Cuadrado-Tejedor
Irene
I
de Miguel
Marta
M
Pérez-González
Carolina
C
García-Barroso
Ana
A
Ugarte
Ander
A
Estella-Hermoso de Mendoza
Elena
E
Sáez
Maria
M
Espelosin
Susana
S
Ursua
WuXi Apptec (Tianjin) Co. Ltd., TEDA, No. 111 HuangHai Road, Fourth Avenue, Tianjin 300456, PR China.
Tan
T
Haizhong
WuXi Apptec (Tianjin) Co. Ltd., TEDA, No. 111 HuangHai Road, Fourth Avenue, Tianjin 300456, PR China.
Wu
W
Wei
WuXi Apptec (Tianjin) Co. Ltd., TEDA, No. 111 HuangHai Road, Fourth Avenue, Tianjin 300456, PR China.
Xu
X
Musheng
Ana
A
Garcia-Osta
Julen
J
Oyarzabal
D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D056572:Histone Deacetylase Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006655:Histone Deacetylases